Test for oxidative damage in Alzheimer's
PET scans and Alzheimer's Disease
Genetic testing could detect Alzheimer's
Biological Function of APP and Alzheimer's Disease ... Tsunao Saitoh
Alzheimer researcher Saitoh murdered
Arrest of Gajdusek, Murder of Saitoh

Test for oxidative damage in Alzheimer's

M A Smith, G Perry P L Richey, L M Sayre, V E Anderson, M F Beal & N Kowall
Nature 382, 120-121 (1996)

Perry et al. describe a histological technique for the detection of oxidative damage in the brains of people who suffered from Alzheimer's disease. The technique, based on free carbonyl detection, allows the exact determination of the subcellular location of oxidative damage, and shows the widespread extent of damage in patients with the condition.

Positron-Emission Tomography and Alzheimer's Disease

July 12, 1996 -- New England Journal of Medicine, Volume 335, Number 3

Reiman et al. (March 21 issue) (1) conclude that abnormalities in glucose metabolism, evaluated by positron-emission tomography (PET) in asymptomatic subjects homozygous for the (epsilon)4 allele for apolipoprotein E, provide preclinical evidence of Alzheimer's disease. The (epsilon)4 allele is highly prevalent not only in patients with Alzheimer's disease but also in those with atherosclerotic vascular disease, including ischemic cerebrovascular disease and vascular dementia. (2,3,4) The PET abnormalities cannot be used to distinguish vascular dementia (formerly called multi-infarct dementia) from Alzheimer's disease. (5,6) Thus, apolipoprotein E genotyping, PET, or the two combined may not be reliable tools for confidently diagnosing presymptomatic Alzheimer's disease. In fact, healthy persons carrying two copies of the (epsilon)4 allele and thought to have Alzheimer's disease on the basis of brain abnormalities detected by PET may actually have unrecognized atherosclerotic cerebrovascular disease. Juan Pedro-Botet, M.D. Juan Rubies-Prat, M.D. Hospital del Mar 08003 Barcelona, Spain References 1. Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer's disease in persons homozygous for the (epsilon)4 allele for apolipoprotein E. N Engl J Med 1996;334:752-8. Return to: Text 2. Pedro-Botet J, Senti M, Nogues X, et al. Lipoprotein and apolipoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke 1992;23:1556-62. Return to: Text 3. Couderc R, Mathieux F, Bailleul S, Fenelon G, Mary R, Fermanian J. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke 1993;24:661-4. Return to: Text 4. Frisoni GB, Geroldi C, Bianchetti A, et al. Apolipoprotein E (epsilon)4 allele frequency in vascular dementia and Alzheimer's disease. Stroke 1994;25:1703-4. Return to: Text 5. Duara R, Barker W, Loewenstein D, Pascal S, Bowen B. Sensitivity and specificity of positron emission tomography and magnetic resonance imaging studies in Alzheimer's disease and multi-infarct dementia. Eur Neurol 1989;29:Suppl 3:9-15. Return to: Text 6. Butler RE, Costa DC, Katona CLE. PET and SPECT imaging in the dementias. In: Murray IPC, Ell PJ, eds. Nuclear medicine in clinical diagnosis and treatment. Edinburgh, Scotland: Churchill Livingstone, 1994:613-27. Return to: Text The authors reply: To the Editor: Alzheimer's dementia is typically characterized by bilateral reductions in glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal regions. (1) In contrast, vascular dementia is characterized by a variable pattern of reductions in glucose metabolism. These reductions are often focal, scattered, and asymmetric; they appear to be related to the location of infarcts. (2) Algorithms developed at the University of Michigan and used in our study to generate spatially standardized, three-dimensional surface-projection brain images improve the ability to detect the pattern of hypometabolism typically associated with Alzheimer's disease and distinguish it from those associated with vascular dementia and other forms of cerebrovascular disease. (3) Persons homozygous for the (epsilon)4 allele for apolipoprotein E appear to have an especially high risk of Alzheimer's dementia. In the original case-control study, 91 percent of (epsilon)4 homozygotes had Alzheimer's dementia by the age of 80. (4) In our study, a cognitively normal group of (epsilon)4 homozygotes in their 50s and early 60s had bilateral reductions in glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as an older group of patients with Alzheimer's dementia. This group had few risk factors for ischemic cerebrovascular disease other than the (epsilon)4 allele and no indication of cerebrovascular disease on the basis of history, neurologic examination, or T1-weighted magnetic resonance images. Although the (epsilon)4 allele is a risk factor for both cardiovascular disease and Alzheimer's dementia, it remains to be determined whether this allele increases the risk of these disorders by the same or different mechanisms. The (epsilon)4 allele may be a risk factor for vascular dementia and other forms of ischemic cerebrovascular disease, but postmortem studies are needed to address the potentially confounding effect of coexisting Alzheimer's disease. Clinically, apolipoprotein E genotyping and PET are not indicated to determine a healthy person's risk of Alzheimer's dementia. At this time, they cannot predict with sufficient certainty a person's risk of this disorder, they cannot predict with sufficient accuracy when symptoms might develop in a person at risk, and they do not indicate what measures might be taken to address the potential problem. Together, these tests promise to help researchers characterize the brain changes that herald the onset of Alzheimer's dementia; they may offer a relatively rapid way to assess future treatments to prevent this devastating disorder. Eric M. Reiman, M.D. Good Samaritan Regional Medical Center Phoenix, AZ 85006 Richard J. Caselli, M.D. Mayo Clinic Scottsdale, AZ 85259 References 1. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE. A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 1995;36:1238-48. Return to: Text 2. Heiss W-D, Podreka I. Cerebrovascular disease. In: Wagner HN, Szabo Z, Buchanan JW, eds. Principles of nuclear medicine. Philadelphia: W.B. Saunders, 1995:531-48. Return to: Text 3. Burdette JH, Minoshima S, Borght TV, Tran DD, Kuhl DE. Alzheimer disease: improved visual interpretation of PET images by using three-dimensional stereotaxic surface projections. Radiology 1996;198:837-43. Return to: Text 4. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-3. Copyright 1996 by the Massachusetts Medical Society

Preliminary study shows genetic testing could detect Alzheimer's

Jul 12, 1996
Nando.net and Associated Press

DURHAM, N.C. -- A new genetic test to detect Alzheimer's disease may bolster efforts to treat the crippling neurological disease, according to a Duke University scientist.

A definitive diagnosis would make it easier for doctors and family members to plan for the care of Alzheimer's patients, said Dr. Allen Roses, who is leading Duke's research into the genetics of Alzheimer's.

Roses thinks his team's genetic discoveries -- which were patented by Duke and licensed to test manufacturer Athena Neurosciences of California -- have produced an extremely accurate diagnostic tool. "If I had a patient who tested positive, I would tell them that the probability this is Alzheimer's is very high," Roses said.

If follow-up studies support the Duke findings -- to be published Saturday in the British medical journal The Lancet -- the test could become the first reliable Alzheimer's test. Currently, the only way a doctor can accurately diagnose the disease is by examining brain tissue after an autopsy.

Lindsay Farrer, a researcher at Boston University School of Medicine, called Roses' findings "exciting and interesting" but said more research needs to be done. Farrer was chairman of the committee that recommended against routine use of the diagnostic test. The patients in Roses' test -- who were followed over a long period of time -- may not represent the typical patient who shows up at a doctor's office complaining of memory loss, he said.

"Before it is applied in any doctor's office, we need studies to see if its predictive value is as high as Dr. Roses says it is," he said.

The test, which has been on the market since March, detects the presence of a gene known as APOE type 4 that Duke researchers first linked to Alzheimer's in 1993. The manufacturer cites statistics and estimates to back its claims of the test's accuracy, but medical experts have been reluctant to endorse its widespread use until more solid data was available.

So Roses sought confirmation in his center's "brain bank", a collection of frozen brain tissue samples. The study marked the first time researchers used actual autopsy results to confirm the findings of a diagnostic Alzheimer's test. They performed genetic tests on brain samples from 67 suspected Alzheimer's patients and found that every patient who tested positive for the gene had autopsy-confirmed Alzheimer's.

The test's shortcoming is that a negative finding tells the patients virtually nothing, Roses said. All of the patients who turned out not to have Alzheimer's tested negative for the gene -- but so did 25 percent of the patients with the disease. "It doesn't mean a thing," he said of the negative tests.

Although no effective treatment exists, doctors and advocates for Alzheimer's patients agree that an accurate diagnostic test would allow them to better manage patients with the unique type of memory loss and confusion the disease causes. The $200 test could mean patients would not have to undergo a battery of expensive tests in search of a diagnosis.

About 4 million Americans suffer from suspected Alzheimer's, but about 15 percent of those diagnosed with it actually suffer from another condition that produces similar symptoms.

Unlike other forms of dementia, Alzheimer's "erases" a person's memory, beginning with recent events and working backward, said Alice Watkins, director of the Alzheimer's Association of Eastern North Carolina. She called the Duke findings "exciting" but preliminary.

Roses agreed that the findings need to be confirmed. "We are talking about small numbers, which is why it is labeled an early report and why it needs to be confirmed," he said. Still, he thinks his study -- along with the unpublished results of several others -- should begin to satisfy skeptics who advised against the routine use of the test in a November article in the influential Journal of the American Medical Association.

Biological Function of APP and Alzheimer's Disease

Alzheimer's Disease Review 1, 30-36, 1996
Tsunao Saitoh and Inhee Mook-Jung
Dept.Neurosciences, School of Medicine, UCSD

Dr. Saitoh was murdered on May 7, 1996. An obituary accompanies this article.


The presence of mutations around the Abeta sequence in APP provides strong argument for the involvement of APP, and Abeta in particular, in pathogenesis of Alzheimer's disease (AD). In vitro studies demonstrated that Abeta may cause neuronal death, supporting the hypothetical involvement of Abeta in neurodegeneration in AD. However, concentrations of Abeta required for neuronal death are nonphysiologically high. Nevertheless, the predominant idea in the field is that it is sufficient to postulate Abeta as a major culprit in AD development. The question we pose is whether the potentially important involvement of Abeta precludes the etiological (primary) involvement (not pathological, i.e., secondary) of APP functions. We do not have an adequate answer to this question. Current knowledge about APP functions indicates that APP is critically required for the maintenance of neuronal and synaptic structure and function. Because AD is a disease of neuronal and synaptic deterioration, APP may be involved during the course of AD pathogenesis, perhaps secondarily. To ponder the question whether APP may be etiologically involved in AD, much needs to be learned about APP functions. This article is intended to provide a foundation for this challenging task.


A major feature of Alzheimer's disease (AD) is the formation of senile plaques in a selected area of the brain. An amyloid deposit composed mainly of beta-amyloid peptide (Abeta) occupies the plaque center. Abeta is a peptide of 40 to 43 residues derived from a larger amyloid precursor protein, APP [Selkoe, 1994]. Genetic studies have provided evidence that APP mutations in the region critical for Abeta generation are tightly associated with familial AD (FAD) [Hardy, 1994]. Furthermore, transgenic animals with an APP minigene containing a mutation develop Abeta deposition in the brain [Games et al., 1995]. Thus, Abeta has been a focus of intensive investigation toward the understanding of AD.

APP is a transmembrane protein with various isoforms that result from alternative splicing [Selkoe, 1994]. APP also exists as secreted forms. By cleavage in the Abeta region of APP, the long N-terminal fragment (secreted APP, sAPP) is secreted into the extracellular space. It is found in plasma and cerebrospinal fluid [Ghiso et al., 1989; Podlisny et al., 1990]. Considering the abundance of both membrane-bound APP and sAPP, they are likely to have significant biological functions. Several APP functions have been suggested. Membrane-bound APP has been suggested to have a receptor-like structure [Kang et al., 1987], with the cytoplasmic domain capable of complexing with a GTP-binding protein [Nishimoto et al., 1993]. Membrane-embedded full-length APP might also have a cell adhesion function [Qiu et al., 1995]. Conversely, proposed functions for sAPP include the regulation of blood coagulation [Cole et al., 1990; Smith et al., 1990; Van Nostrand et al., 1990], wound-healing [Cunningham et al., 1991], extracellular protease activity [Oltersdorf et al., 1989; Van Nostrand et al., 1989], neurite extension [Jin et al., 1994; Robakis et al., 1990], cell adhesiveness [Schubert et al., 1989a], cell growth, [Bhasin et al., 1991; Saitoh et al., 1989], and differentiation [Araki et al., 1991; Milward et al., 1992; Yamamoto et al., 1994].

Here it may be worth entertaining a hypothesis that APP functions may be etiologically involved in certain cases of AD. First, the APP mutation identified by Goate et al. [1991] affects the gamma-secretase-dependent cleavage of APP, producing longer Abeta 1-42 instead of Abeta 1-40 [Suzuki et al., 1994]. Does this affect APP's function? Perhaps. There are two possibilities. Abeta has been shown to bind APP [Strittmatter et al., 1993b], raising the possibility that "APP function" may be regulated by Abeta, and that Abeta 1-40 and Abeta 1-42 might have different regulatory activities. The second possibility is that APP's function is the sum of "trophic APP" and "atrophic Abeta" and that Abeta 1-42 is more atrophic than Abeta 1-40. The second mutation in APP [Mullan et al., 1992] affects the beta-secretase-dependent cleavage of APP producing more Abeta [Cai et al., 1993; Citron et al., 1992]. In this case, the potential involvement of APP's function is explained either by postulating physical binding of Abeta with APP or biological interaction of Abeta with APP. Thus, possibly, knowledge about normal functions of APP is crucial in understanding the etiology of AD. At least there is evidence that abnormality in APP processing and eventual APP dysfunction, aside from amyloid accumulation, contributes to neurodegeneration.

APP expression

Many different types of cells synthesize APP. In neurons it is abundantly located in the synaptic zone [Schubert, 1991]. Different cell types produce different isoforms of APP. Differentiated neurons produce mainly the APP695 form whereas non-neuronal cells produce the Kunitz-type protease inhibitor (KPI)-containing forms of APP [Selkoe, 1994]. An APP lacking the exon 15 sequence contains a chondroitin sulfate (CS) glycosaminoglycan (GAG) chain near the N-terminus of the Abeta region [Pangalos et al., 1995]. The presence of exon 15 disrupts the consensus sequence for CS chain attachment. Because the CS attaches close to the beta-secretase site, Abeta production might be affected by this modification that hides the N-terminal cleavage site from proteolytic processing. This form of APP is produced abundantly in astrocytes, but is not present in neuronal cells, oligodendrocytes, and microglia in culture [Shioi et al., 1995]. cAMP treatment blocks the production of this type of APP in the N2a neuroblastoma cell without affecting APP expression. Thus, available data suggest that APP in the presence or absence of the KPI domain and exon 15 are functionally different from one another and are differentially regulated. Abnormal APP splicing which results in altered expression of APP isoforms may contribute to AD [Jacobsen et al., 1991; Johnson et al., 1990; Konig et al., 1991; Neve et al., 1990; Rockenstein et al., 1995; Tanaka et al., 1992]. Considering that APP695 is a brain-specific isoform of APP, one can speculate that the secreted form of APP695 (sAPP695) is a key molecule involved in some brain-specific mechanisms.

Using a battery of different antibodies to various regions of APP, Cole et al. [1991] and Joachim et al. [1991] have shown that N-terminal as well as C-terminal fragments of APP accumulate in the periphery of the senile plaques. This probably indicates the presence of full-length APP in the swollen neurites surrounding the plaque core, which is consistent with the finding that APP undergoes fast anterograde axonal transport [Koo et al., 1989]. These findings have raised the possibility that N-terminal fragments of APP play a significant role in the aberrant sprouting reaction observed in the vicinity of the plaques. We have shown APP to colocalize with GAP-43 in both neuritic plaques [Masliah et al., 1992b] and growth cones [Masliah et al., 1992a] and to be concentrated at the synapses. If APP has a trophic or maintenance function in the synapses, an alteration in the processing of APP, and consequently an alteration of the concentration and activity of APP695 in the synapses, could lead to synapse loss and neuronal death, as observed in AD. Conversely, APP might be involved in the sprouting reactions of remaining neurons, which is also observed in AD. To see whether this is the case, a full understanding of the physiological functions of APP is necessary.

Role of proteoglycans in neurite outgrowth

sAPP and its fragments fulfill the definition of the neurotrophic factor by supporting neuron survival and promoting neurite outgrowth. Several regions of APP are potentially involved in trophic functions. APP binds heparin as do many trophic proteins [Schubert et al., 1989b]. Two heparin binding domains (HBD) in the N-terminal region of APP and one heparin binding consensus sequence within the Abeta region have been reported [Multhaup, 1994; Snow et al., 1995]. Small [1996] discusses the significance of the HBD in detail. Although extracellular matrix molecules are important for neurite outgrowth in the developing brain, APP may also bind to cell surface heparan sulfate proteoglycan (HSPG). When heparitinase or heparin is coincubated with sAPP in B103 neuronal cell culture, sAPP binding to cells is reduced [Ninomiya et al., 1994], and the APP effect on neurite extension is reduced in a dose-dependent manner. Small negatively charged ions as well as chlorate can block the trophic effect of sAPP. Further, HSPG from a certain developmental stage can bind to sAPP [Small et al., 1994], suggesting that the degree of sulfation on GAG or the equilibrium of charge in the extracellular space might regulate the affinity of sAPP to its hypothetical receptor. One possible model for the involvement of cell surface HSPG in the trophic function of sAPP is that the binding of HSPG with sAPP increases the affinity of sAPP to its receptor and facilitates the eventual induction of a second messenger cascade. This mode of HSPG involvement is similar to the basic fibroblast growth factor (bFGF) receptor. bFGF binds to HSPG and is transferred to the receptor, which activates a second messenger cascade [Olwin and Rapraeger, 1992). In spite of these data for the involvement of proteoglycan in the regulation of APP functions, it seems that proteoglycan plays only a modulatory role, and the major determinants of APP functions are within its protein sequence.

Role of sAPP and its fragments on neurite outgrowth

Functional mapping of APP shows that the RERMS domain in the middle portion of APP is responsible for growth stimulation on the A-1 fibroblast [Ninomiya et al., 1993] as well as for neurite extension in clonal B103 neuronal cells [Jin et al., 1994] and primary cortical neurons [Yamamoto et al., 1994]. As the RERMS domain (APP 319-335) sequence is highly conserved in different species and is present in all the isoforms of APP, the biological role of this domain might be important. This domain of APP, in addition to being neuritotropic, could increase synaptic density and memory retention in vivo [Roch et al., 1994] and could reduce neurological damage in ischemia [Bowes et al., 1994]. Also, sAPP protects neurons from hypoxia-induced cell death and calcium-mediated glutamate toxicity [Mattson et al., 1993]. One possible mechanism of neurotrophic function for sAPP could be the binding of sAPP to a cell surface receptor that can activate a signal transduction cascade inside the cell. The supportive evidence for the presence of the sAPP receptor is threefold. First, the binding assay using 125I-labeled sAPP on B103 cells shows 105 binding sites per cell with Kd values of 20 ± 5 nM. The binding is sequence specific and the RERMS sequence is essential for binding activity [Saitoh and Roch, 1995]. Second, sAPP induces phosphatidyl inositol turnover [Jin et al., 1994], activates MAPK [Greenberg et al., 1994], and affects Ca2+ homeostasis [Mattson et al., 1993], signature biochemical reactions for the presence of receptor activation. Considering that the RERMS sequence is involved in both neurite extension and cell surface binding, the neurotrophic function of sAPP is likely through a cell surface receptor that recognizes a specific ligand and induces the signal transduction cascade inside the cell. Third, sAPP activates membrane-bound guanylate cyclase [Barger and Mattson, 1995], and exogenously provided cGMP mimics sAPP's function [Barger et al., 1995]. Combining the above results with the abundant presence of APP in the synaptic zone, sAPP very likely has a trophic or maintenance function in synapses. An alteration in APP processing might cause a biologically inadequate concentration or activity of sAPP in the synapses which could lead to synaptic loss and neuronal death. sAPP might also be involved in sprouting reactions of the remaining neurons which in turn could lead to or accelerate the pathogenesis of AD [Ihara, 1988].

Induction of signal transducing pathways by sAPP and its fragments

Biological effects related to cell growth and neurotrophic function of sAPP have been intensively studied. Less is known, however, about the intracellular cascades that mediate these effects. As a pharmacological approach, genistein, a tyrosine kinase inhibitor, and orthovanadate, an inhibitor of phosphotyrosine phosphatase, have been tested in conjunction with sAPP in B103 cells [Saitoh et al., 1995]. Genistein greatly potentiates sAPP's effect on neurite outgrowth in B103 cells whereas orthovanadate abolishes the sAPP effect, suggesting that sAPP action is associated with tyrosine phosphorylation. Consistent with this finding, sAPP induces a 10-fold increase of mitogen-activated protein kinase (MAPK) activity in PC12 cells, which is blocked by a dominant-negative ras [Greenberg et al., 1994]. In general, MAPKs are activated by a variety of trophic factors and regulate many substrates involved in gene transcription, cell growth, and signaling.

The levels of intracellular Ca2+ and cGMP are also regulated by sAPP. The sAPP treatment on cultured hippocampal neurons lowers intracellular Ca2+ concentration rapidly [Mattson et al., 1993] and elevates the cGMP level [Barger et al., 1995]. The effect is mimicked by the membrane-permeable analogue of cGMP. Further investigation to understand the mechanism of the sAPP effect on cGMP and calcium homeostasis has shown that the sAPP effect is through a membrane-associated guanylate cyclase, not a soluble (cytosolic) guanylate cyclase [Barger and Mattson, 1995]. Because cGMP can protect neurons against glutamate toxicity, cGMP induction may play an important role in sAPP's function to antagonize glutamate toxicity. Taken together, sAPP could regulate several pathways of signal transduction. When abnormality in APP function occurs, it might cause a disruption of intracellular signaling, leading to AD pathogenesis. In effect, grossly abnormal signal transduction systems are observed in the early phase of AD before full-blown pathology develops [Saitoh et al., 1991].

Neurotoxic effect of Abeta

To explain massive neuronal loss in the brain of AD patients, several models have been proposed placing Abeta as a principal culprit [Cai et al., 1993; Citron et al., 1992; Hardy et al., 1992; Joachim and Selkoe, 1992; Kosik, 1992; Mattson et al., 1992; Pike et al., 1993; Yankner et al., 1989, 1990a,b]. Possible mechanisms of Abeta toxicity include calcium channel formation [Arispe et al., 1994], anomalies in potassium channels [Etcheberrigaray et al., 1994], kinase activation [Zhang et al., 1994], generation of free radicals [Behl and Schubert, 1993], and enhancement of glutamate toxicity [Mattson et al., 1992]. Because APP plays a role in cell growth and neuronal maintenance and differentiation, understanding the relationship between sAPP's neurotrophic function and Abeta neurotoxicity is important. sAPP treatment could reduce the effect of Abeta on neurons [Goodman and Mattson, 1994] which suggests that the neurotrophic effect of sAPP is sufficient to overcome Abeta toxicity under normal conditions.

In this context, note that the Abeta peptide is not a pathological product but a physiological product found in the culture-conditioned medium or cerebrospinal fluid [Haass et al., 1992; Seubert et al., 1992; Shoji et al., 1992]. This makes it possible that Abeta has a physiological function. Although the Abeta peptide has been shown to be toxic in extreme conditions [Yankner et al., 1990a,b], we hypothesize that the real function of Abeta is to negatively control synaptic function after transport to the axonal terminals. Experiments using cloned neuronal receptors expressed in oocytes show that Abeta weakly activates tachykinin receptors [Kimura and Schubert, 1993]. But in the presence of NMDA and AMPAñkainate glutamate receptors, Abeta-induced tachykinin receptor responses are greatly enhanced. Glutamate and Abeta together also induce inositol trisphosphate (IP3) accumulation and increases in intracellular Ca2+. These observations suggest that in the presence of glutamate, Abeta can activate tachykinin receptors and phosphatidyl inositol turnover. Abeta may therefore act as a neuromodulatory peptide. These results tend to agree with the enhancement of glutamate toxicity by Abeta [Mattson et al., 1992].

How may APP dysfunction be involved in AD pathogenesis? A hypothesis

Numerous literature firmly establishes both the neurotrophic and neurotoxic activities of APP. What might be the significance of these activities in the pathophysiology of AD? The currently predominant hypothesis for the etiology of AD is that Abeta toxicity is responsible for neurodegeneration in this disease. However, Abeta per se might not be sufficient to cause neuronal death and dementia. The release of Abeta protein by cultured cells under normal physiological conditions raises the question of how and why the Abeta peptide adopts the beta-pleated amyloid conformation that may be neurotoxic. In this respect, the interaction of Abeta with other molecules might yield crucial information. In addition to apolipoprotein E (apoE) [Strittmatter et al., 1993a], one of these molecules that interact with Abeta is APP itself [Goldgaber et al., 1993]. Hence, one possibility is that APP may affect the Abeta structure and its toxicity, and, conversely, the trophic sAPP activity might be affected by the Abeta peptide. In any event, it is likely that the balance between the trophic sAPPalpha, generated by the alpha-secretase pathway, and the toxic Abeta, generated through the beta-secretase pathway, affects the homeostasis of neurons. Especially, because the alpha-secretase pathway excludes the possibility of Abeta formation, the regulation of this pathway should be crucially important in understanding the biological significance of the two pathways of APP processing. Many activities attributed to sAPP as discussed above could be influenced by the simultaneous signal pathways triggered by Abeta peptide. Maintaining the balance between the two major pathways of APP, one leading to the "physiological" secretion of the N-terminal portion (alpha-secretase pathway), and the other leading to the secretion of the Abeta peptide (beta-secretase pathway), seems important.

Both sAPP and Abeta protein may play key roles in AD pathology although the molecular mechanisms by which they become involved in the neurodegeneration are still unclear. Whereas the Abeta peptide might be neurotoxic when deposited in the amyloid form, an alteration of the neurotrophic activity of the secreted form of its precursor might also be considered as an event potentially leading to dementia. Thus, one working hypothesis on the role of APP in the pathogenesis of AD can be the following: APP is an important protein involved in the regulation of synaptic function and neuronal homeostasis. This regulatory role of APP is manifested in two domains of the molecule, the RERMS/neurotrophic domain in the N-terminal secreted moiety, and the Abeta/neurotoxic domain that can form amyloid under pathological conditions. In AD patients, abnormal metabolism and compartmentalization of APP leads to an imbalance of two APP functions and eventually to alteration in the maintenance of synapses and the homeostasis of neurons. This, in turn, could lead to the massive neuronal loss and reactive sprouting observed in AD brains. In conclusion, APP is both a neurotrophic and a neurotoxic protein whose activities are represented by small domains in the middle and carboxyl terminal portions of APP, respectively. Perhaps the balance between these neurotrophic and neurotoxic activities of APP may not be properly controlled in AD. The balance may be regulated by controlling the pathways by which APP is processed or by controlling the availability of molecules interacting with APP and Abeta, such as apoE [Strittmatter et al., 1993a], NACP [Uéda et al., 1993], and alpha1-antichymotrypsin [Abraham and Potter, 1989]. At present, we have only fragmented knowledge about APP functions, and understanding the complete picture requires further investigations.


We thank Robert Davignon and Patty Melendrez for their editorial help in the preparation of this article. The research from the authorsí laboratory, which is summarized in this article, has been supported by a Zenith Award from the Alzheimer's Association and by a National Institutes of Health grant (NS28121).


Abraham, C. R. and Potter, H. (1989) The protease inhibitor, alpha1-antichymotrypsin, is a component of the brain amyloid deposits in normal aging and Alzheimer's disease. Ann Med, 21, 77ñ81.

Araki, W., Kitaguchi, N., Tokushima, Y., Ishii, K., Aratake, H., Shimohama, S., Nakamura, S. and Kimura, J. (1991) Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun 181, 265ñ271.

Arispe, N., Pollard, H. and Rojas, E. (1994) beta-Amyloid Ca(2+)-channel hypothesis for neuronal death in Alzheimer's disease. Mol Cell Biochem 140, 119ñ125.

Barger, S. and Mattson, M. (1995) The secreted form of the Alzheimer's beta-amyloid precursor protein stimulates a membrane-associated guanylate cyclase. J Biochem 311, 45ñ47.

Barger, S., Fiscus, R., Ruth, P., Hofmann, F. and Mattson, M. (1995) Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of beta-amyloid precursor. J Neurochem 64, 2087ñ2096.

Behl, C. and Schubert, D. (1993) Heat shock protects nerve cells from amyloid beta protein toxicity. Neurosci Lett 154, 1ñ4.

Bhasin, R., Van Nostrand, W.E., Saitoh, T., Donets, M.A., Barnes, E.A., Quitschke, W.W. and Goldgaber, D. (1991) Expression of active secreted forms of human amyloid beta-protein precursor by recombinant baculovirus-infected insect cells. Proc Natl Acad Sci USA 88, 10307ñ10311.

Bowes, M.P., Masliah, E., Otero, D.A.C., Zivin, J.A. and Saitoh, T. (1994) Reduction of neurological damage by a peptide segment of the amyloid beta/A4-protein precursor (APP) in a rabbit spinal cord ischemia model. Exp Neurol 129, 112ñ119.

Cai, X.D., Golde, T.E. and Younkin, S.G. (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259, 514ñ516.

Citron, M., Oltersdorf, T., Haass , C., McConlogue, L., Hung, A.Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I. and Selkoe, D.J. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672ñ674.

Cole, G.M., Galasko, D., Shapiro, I.P. and Saitoh, T. (1990) Stimulated platelets release amyloid beta-protein precursor. Biochem Biophys Res Commun 170, 288ñ295.

Cunningham, J. M., Kaiser, K. K. and Sanes, J. R. (1991) Rostrocaudal variation of fiber type composition in rat intercostal muscles. Histochemistry 95, 513ñ517.

Etcheberrigaray, R., Ito, E., Kim, C. and Alkon, D. (1994) Soluble beta-amyloid induction of Alzheimer's phenotype for human fibroblast K+ channels. Science 264, 276ñ279.

Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Liebowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala, M., Mucke, L., Paganini, E., Penniman, E., Power, M., Schenk, D., Seubert, P., Snyder, B., Soriano, F., Tan, H., Vitale, J., Wadsworth, S., Wolozin, B. and Zhao, J. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing 717VÆF beta-amyloid precursor protein. Nature 373, 523ñ527.

Ghiso, J., Tagliavlni, F., Timmers, W.F. and Frangione, B. (1989) Alzheimer's disease amyloid precursor protein is present in senile plaques and cerebrospinal fluid: Immunohistochemical and biochemical characterization. Biochem Biophys Res Comm 163, 430ñ437.

Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704ñ706.

Goldgaber, D., Schwarzman, A., Bhasin, R., Gregori, L., Schmechel, D., Saunders, A., Roses, A. and Strittmatter, W. (1993) Sequestration of amyloid beta peptide. Ann NY Acad Sci 695, 139ñ143.

Goodman, Y. and Mattson, M. (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exptl Neuro 128, 1ñ12.

Greenberg, S.M., Koo, E.H., Selkoe, D.J., Qiu, W.Q. and Kosik, K.S. (1994) Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. Proc Natl Acad Sci USA 91, 7104ñ7108.

Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberburg, I., Koo, E.H., Schenk, D., Teplow, D.B. and Selkoe, D.J. (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature (London) 359, 322ñ325.

Hardy, J. (1994) Alzheimer's disease. Clinical molecular genetics. Clin Geriatr Med 10, 239ñ247.

Hardy, J.A. and Higgins, G.A. (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184ñ185.

Ihara, Y. (1988) Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res 459, 138ñ144.

Jacobsen, J.S., Blume, A.J. and Vitek, M.P. (1991) Quantitative measurement of alternatively spliced amyloid precursor protein mRNA expression in Alzheimer's disease and normal brain by S1 nuclease protection analysis. Neurobiol Aging 12, 585ñ592.

Jin, L.-W., Ninomiya, H., Roch, J.-M., Schubert, D., Otero, D.A.C. and Saitoh, T. (1994) Peptides containing RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14, 5461ñ5470.

Joachim, C., Games, D., Morris, J., Ward, P., Frenkel, D. and Selkoe, D. (1991) Antibodies to non-beta regions of the beta-amyloid precursor protein detect a subset of senile plaques. Am J Pathol 138, 373ñ384.

Joachim, C. and Selkoe, D. (1992) The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease. Alzheimer Disease and Associated Disorders 6, 7ñ34.

Johnson, S.A., McNeil, T., Cordell, B. and Finch, C.E. (1990) Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease. Science 248, 854ñ857.

Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, M.J., Masters, C.L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K. and Müller-Hill, B. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733ñ736.

Kimura, H. and Schubert, D. (1993) Amyloid beta protein activates tachykinin receptors and IP3 accumulation by synergy with glutamate. Proc Natl Acad Sci USA 90, 7508ñ7512.

Konig, G., Salbaum, J.M., Wiestler, O., Lang, W., Schmitt, H.P., Masters, C.L. and Beyreuther, K. (1991) Alternative splicing of the betaA4 amyloid gene of Alzheimer's disease in cortex of control and Alzheimer's disease patients. Mol Brain Res 9, 259ñ262.

Koo, E., Sisodia, S., Archer, D., Martin, L., Weidemann, A., Beyreuther, K., Fischer, P., Masters, C. and Price, D. (1989) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87, 1561ñ1565.

Kosik, K.S. (1992) Alzheimer's disease: A cell biological perspective. Science 256, 780ñ783.

Masliah, E., Mallory, M., Ge, N. and Saitoh, T. (1992a) Amyloid precursor protein is localized in growing neurites of neonatal rat brain. Brain Res 593, 323ñ328.

Masliah, E., Mallory, M., Hansen, L., Alford, M., DeTeresa, R., Terry, R.D., Baudier, J. and Saitoh, T. (1992b) Localization of amyloid precursor protein in GAP-43 immunoreactive aberrant sprouting neurites in Alzheimer's disease. Brain Res 574, 312ñ316.

Mattson, M.P., Cheng, B., Culwell, A.R., Esch, F.S., Lieberburg, I. and Rydel, R.E. (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10, 243ñ254.

Mattson, M.P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I. and Rydel, R.E. (1992) beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12, 376ñ398.

Milward, E.A., Papadopoulos, R., Fuller, S.J., Moir, R.D., Small, D., Beyreuther, K. and Masters, C.L. (1992) The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9, 129ñ137.

Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B. and Lannfelt, I. (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nature genet 1, 345ñ347.

Multhaup, G. (1994) Identification and regulation of the high affinity binding site of the Alzheimer's disease amyloid protein precursor (APP) to glycosaminoglycans. Biochimie 76, 304ñ311.

Neve, R.L., Rogers, J. and Higgins, G.A. (1990) The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain. Neuron 5, 329ñ338.

Ninomiya, H., Roch, J.-M., Jin, L.-W. and Saitoh, T. (1994) Secreted form of APP binds to two distinct APP binding sites on B103 rat neuronal cells through two different domains, but only one site is involved in trophic activity. J Neurochem 63, 495ñ500.

Ninomiya, H., Roch, J.-M., Sundsmo, M.P., Otero, D.A.C. and Saitoh, T. (1993) Amino acid sequence RERMS represents the active domain of amyloid beta/A4 protein precursor that promotes fibroblast growth. J Cell Biol 121, 879ñ886.

Nishimoto, I., Okamoto, T., Matsuura, Y., Takahashi, S., Okamoto, T., Murayama, Y. and Ogata, E. (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o). Nature 362, 75ñ79.

Oltersdorf, T., Fritz, L.C., Schenk, D.B., Lieberburg, I., Johnson-Wood, K.L., Beattie, E.C., Ward, P.J., Blacher, R.W., Dovey, H.F. and Sinha, S. (1989) The secreted form of the Alzheimer's amyloid precursor with the Kunitz domain is protease nexin-II. Nature (London) 341, 144ñ147.

Olwin, B.B. and Rapraeger, A. (1992) Repression of myogenic differentiation by aFGF, bFGF and K-FGF is dependent on cellular heparan sulfate. J Cell Biol 118, 631ñ639.

Pangalos, M., Shioi, J. and Robakis, N. (1995) Expression of the chondroitin sulfate proteoglycans of amyloid precursor (appican) and amyloid precursor-like protein 2. J Neurochem 65, 762ñ769.

Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W. (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: The role of peptide assembly state. J Neurosci 13, 1676ñ1687.

Podlisny, M.B., Mammen, A.L., Schlossmacher, M.G., Palmert, M.R., Younkin, S.G. and Selkoe, D.J. (1990) Detection of soluble forms of the beta-amyloid precursor protein in human plasma. Biochem Biophys Res Commun 167, 1094ñ1101.

Qiu, W., Ferreira, A., Miller, C., Koo, E. and Selkoe, D. (1995) Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci 15, 2157ñ2167.

Robakis, N.K., Altstiel, L.D., Refolo, L.M. and Anderson, J.P. (1990) Function and metabolism of the protease inhibitor-containing Alzheimer amyloid precursors, in Molecular Biology of Alzheimer's Disease. (T. Miyatake, D.J. Selkoe and Y. Ihara, ed.), pp. 179ñ188, Elsevier Science Publishers B.V., Amsterdam.

Roch, J.-M., Masliah, E., Roch-Levecq, A.-C., Sundsmo, M.P., Otero, D.A.C., Veinbergs, I. and Saitoh, T. (1994) Increased synaptic density and memory retention by a peptide representing the active domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci USA 91, 7459ñ7454.

Rockenstein, E., McConlogue, L., Tan, H., Power, M., Masliah, E. and Mucke, L. (1995) Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease. J Biol Chem 270, 28257ñ28267.

Saitoh, T., Sundsmo, M., Roch, J.-M., Kimura, N., Cole, G., Schubert, D., Oltersdorf, T. and Schenk, D.B. (1989) Secreted form of amyloid beta-protein precursor is involved in the growth regulation of fibroblasts. Cell 58, 615ñ622.

Saitoh, T., Masliah, E., Jin, L.W., Cole, G.M., Wieloch, T. and Shapiro, I.P. (1991) Protein kinases and phosphorylation in neurologic disorders and cell death. Lab Invest 64, 596ñ616.

Saitoh, T., Jin, L.-W., Roch, J.-M. and Pawlik, M. (1995) Induction of signal-transducing pathways by APP binding to the cell surface receptor. Research Advances in Alzheimer's Disease and Related Disorders 75, 693ñ699.

Saitoh, T. and Roch, J.-M. (1995) APP-derived peptides with neurotrophic effects. Drug News & Perspect 8, 206ñ215.

Schubert, D. (1991) The possible role of adhesion in synaptic modification. Trends Neurosci 14, 127ñ130.

Schubert, D., Jin, L.-W., Saitoh, T. and Cole, G. (1989a) The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron 3, 689ñ694.

Schubert, D., LaCorbiere, M., Saitoh, T. and Cole, G.M. (1989b) Characterization of a beta-precursor protein which binds heparin and contains tyrosine sulfate. Proc Natl Acad Sci USA 86, 2066ñ2069.

Selkoe, D.J. (1994) Normal and abnormal biology of the beta-amyloid precursor protein. Ann Rev Neurosci 17, 489ñ517.

Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schlosmacher, M., Whaley, J., Swindlehurst, C., McCormack, R., Wolfert, R., Selkoe, D., Lieberburg, I. and Schenk, D. (1992) Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature 359, 325ñ327.

Shoji, M., Golde, T.E., Ghiso, J., Cheung, T.T., Estus, S., Shaffer, L., Cai, X.-D., McKay, D.M., Tintner, R., Frangione, B. and Younkin, S.G. (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258, 126ñ129.

Shioi, J., Pangalos, M., Ripellino, J., Vassilacopoulou, D., Mytilineou, C., Margolis, R. and Robakis, N. (1995) The Alzheimer amyloid precursor proteoglycan (appican) is present in brain and is produced by astrocytes but not by neurons in primary neural cultures. J Biol Chem 270, 11839ñ11844.

Small, D.H., Nurcombe, V., Reed, G., Clarris, H., Moir, R., Beyreuther, K. and Masters, C.L. (1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci 14, 2117ñ2127.

Small, D.H., Clarris, H.L., Williamson, T.G., Reed, G., Key, B., Mok, S.S., Beyreuther, K., Masters, C.L. and Nurcombe, V. (1996) Trophic functions of the amyloid protein precursor of Alzheimer's disease. Alzheimer's Disease Review, In this issue.

Smith, R.P., Higuchi, D.A. and Broze, G.J., Jr. (1990) Platelet coagulation factor XI alpha-inhibitor, a form of Alzheimer amyloid precursor protein. Science 248, 1126ñ1128.

Snow, A., Kinsella, M., Parks, E., Sekiguchi, R., Miller, J., Kimata, K. and Wight, T. (1995) Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin and versican) to the beta-amyloid protein of Alzheimer's disease. Arch Biochem Biophys 320, 84ñ95.

Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S. and Roses, A.D. (1993a) Apolipoprotein E: High avidity binding to beta-amyloid and increased frequency of type 4 allele in late onset familial Alzheimer disease. Proc Natl Acad Sci USA 90, 1977ñ1981.

Strittmatter, W., Huang, D., Bhasin, R., Roses, A. and Goldgaber, D. (1993b) Avid binding of beta A amyloid peptide to its own precursor. Exp Neurol 122, 327ñ334.

Suzuki, N., Cheung, T.T., Cai, X.D., Odaka, A., Otvos, L., Jr., Eckman, C., Golde, T.E. and Younkin, S.G. (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336ñ1340.

Tanaka, S., Liu, L., Kimura, J., Shiojiri, S., Takahashi, Y. and Uéda, K. (1992) Age-related changes in the proportion of amyloid precursor protein mRNAs in Alzheimer's disease, and other neurological disorders. Mol Brain Res 15, 303ñ310.

Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y. and Saitoh, T. (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90, 11282ñ11286.

Van Nostrand, W.E., Schmaier, A.H., Farrow, J.S. and Cunningham, D.D. (1990) Protease nexin-II (amyloid beta-protein precursor): A platelet alpha-granule protein. Science 248, 745ñ748.

Van Nostrand, W.E., Wagner, S.L., Suzuki, M., Choi, B.H., Farrow, J.S., Geddes, J.W., Cotman, C.W. and Cunningham, D.D. (1989) Protease nexin-II, a potent anti-chymotrypsin, shows identity to amyloid beta protein precursor. Nature 341, 546ñ548.

Yamamoto, K., Miyoshi, T., Yae, T., Kawashima, K., Araki, H., Hanada, K., Otero, D.A.C., Roch, J.-M. and Saitoh, T. (1994) The survival of rat cerebral cortical neurons in the presence of trophic APP peptides. J Neurobiol 25, 585ñ594.

Yankner, B.A., Caceres, A. and Duffy, L.K. (1990a) Nerve growth factor potentiates the neurotoxicity of beta amyloid. Proc Natl Acad Sci USA 87, 9020ñ9023.

Yankner, B.A., Dawes, L.R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M.L. and Neve, R.L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245, 417ñ420.

Yankner, B.A., Duffy, L.K. and Kirschner, D.A. (1990b) Neurotrophic and neurotoxic effects of amyloid beta protein: Reversal by tachykinin neuropeptides. Science 250, 279ñ282.

Zhang, C., Lambert, M., Bunch, C., Barber, K., Wade, W., Krafft, G. and Klein, W. (1994) Focal adhesion kinase expressed by nerve cell lines shows increased tyrosine phosphorylation in response to Alzheimer's A beta peptide. J Biol Chem 269, 25247ñ25250.

Figure 1. Two pathways for APP processing define its activity.
The alpha-secretase pathway generates the trophic sAPPalpha exclusively whereas the beta-secretase pathway generates the neurotoxic Abeta and the sAPPbeta that is less trophic than sAPPalpha.

Tsunao Saitoh 1949-1996

Robert Katzman and Leon Thal
Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0624, USA

We tragically lost our friend and colleague, Tsunao Saitoh, Professor of Neurosciences at the University of California San Diego, and his 13 year old daughter, Louille, at about 11 PM on Tuesday May 7, 1996 as they were returning from his laboratory. They were killed at gun point in front of their home. He had spent the evening working and helping his daughter with her homework. This tragedy is deeply felt by his remaining family, his many colleagues, collaborators, and friends.

We were extraordinarily fortunate in recruiting Dr. Saitoh to the UCSD Department of Neurosciences and the Alzheimer Disease Research Center in 1985. Tsunao initially studied changes in protein kinases in brains of Alzheimer patients. Subsequently, he turned his attention to the physiological function of the APP molecule, demonstrating its trophic properties. During these studies, he and his collaborators identified a 17 amino acid active neurotrophic region near the insertion point of the Kunitz sequence. He then discovered a new amyloid component protein (NACP and cloned the NACP gene which is located on chromosome 4 and is present as part of the amyloid core in about four-fifths of the neuritic plaques in Alzheimer brains. He showed that NACP aggregated with the A peptide to form amyloid, in a manner analogous to apolipoprotein E. During the past several months, Dr. Saitoh's laboratory has investigated the possibility that inheritance of a specific allele of NACP might alter susceptibility to the development of Alzheimer's disease. This work was part of a larger scientific effort aimed at identifying genetic factors that might modify the risk of developing Alzheimer's disease in both apolipoprotein E4 positive and negative individuals. At the time of his death he was at the very peak of his productive career. Numerous manuscripts were in preparation when his life was cut short.

Analysis: Arrest of Gajdusek, Murder of Saitoh

Listserve Commentary
22 July 1996

"In the months since Gajdusek's arrest and weeks since Saitoh's murder, as no other explanations have come forward, I have wondered what could have been the motivation, what the intimidation could be about. Certainly the murder of Saitoh and his daughter could have been a mistake. Gajdusek could simply have gone too far in his cultural relativism.

But there are some big money issues in the mix, such as transgenic mice, growth hormone, drug development, and chemical toxin liability. I have become intrigued by Saitoh's interest in the shift in the glutamate - calcium intracellular flux and the resulting shift to amyloid accumulation intracellularly as opposed to an intercellular messenger path.

If it is this excitotoxic process which accelerates the neurodegeneration in Alzheimer's Disease, and also in other neurodegenerative diseases, then I could see a link to BSE. That's the long way around to what Saitoh would have to do with intimidation about BSE. Not the cause, but the mechanisms by which a neurodegenerative process picks up speed, is what I think could be the link. Gajdusek seemed to hope he had the key, from the Papua New Guinea population, for resisting the neurodegeneration of HTLV-1.