Nature Medicine 10, S26–S33 (2004)

Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration

Neurodegenerative diseases can be genetic or sporadic in origin. Genetic analysis has changed the study of the pathogenesis of these disorders by showing the causative functions of rare mutations. Yet, in the most common age-associated neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, the causes of neurodegeneration remain to be clarified. The observations that presenilin modulates proteolysis and turnover of several signaling molecules have led to speculations that pathways that are important in development may contribute to neurodegeneration. In this article, the possibility that these presenilin-regulated molecules may contribute to neurodegeneration is reviewed.

Edward H Koo¹ & Raphael Kopan<sup>2

1</sup> Department of Neurosciences, University of California, San Diego, La Jolla, California 92093.

² Departments of Molecular Biology and Pharmacology and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.

Correspondence should be addressed to Edward H Koo edkoo@ucsd.edu

Published online: 1 July 2004
doi:10.1038/nm1065

In the past decade, studies on familial AD (FAD) cases, the rare inherited autosomal dominant form of AD, have yielded suggestive, if very indirect, clues about sporadic AD. Evidence has shown that mutations in presenilins, a component of the -secretase enzyme complex, and amyloid precursor protein (APP), a presenilin substrate and the precursor of amyloid -protein (A), are the major causes of early-onset FAD. Another disease-predisposing gene, APOE, is also involved in APP metabolism. In parallel, presenilin also has an important role in proteolysis and turnover of various signaling molecules, some of which participate in developmentally important pathways (Fig. 1). Therefore, it has been speculated that molecules or pathways that are crucial in developmental processes may participate in or contribute to neurodegeneration. These pathways may contribute to neuronal and synaptic dysfunction because they are either reactivated or perturbed in late life in ways that contribute to neuronal or synaptic dysfunction.

Fig. 1
		Figure 1 | Schematic showing the multiple physiological functions of presenilin.

The most common age-associated neurodegenerative disorder, AD is characterized by neurofibrillary tangle formation in neuronal perikarya and extracellular deposits of A within senile plaques in the cerebral cortex¹. Reactive astrocytic changes and inflammatory responses frequently accompany the lesions. No less important but much more subtle are loss of neurons and especially synapses in the cortex². Indeed, most investigators now believe that synaptic dysfunction, disconnection or synapse loss, which may precede the development of brain pathology, is the most important cause for the cognitive impairment seen in the disease³.

How the pathological synaptic changes are initiated in the brain is not clear. The leading explanation is the amyloid hypothesis, which states that neuronal dysfunction and death, neurofibrillary degeneration, microglial activation and the full manifestation of Alzheimer's pathology are initiated by A deposition⁴. Since this idea was proposed more than 10 years ago, this still-controversial hypothesis has remained surprisingly intact except for a recent shift in focus away from A aggregates to A in its nonfibrillar or oligomeric state, or 'invisible amyloid'. The reason for this shift is that the aggregated and fibrillar form deposited in senile plaques has not correlated well with measures of cognitive decline, whereas soluble A in its various assembly forms seems to be toxic⁵. In contrast, soluble oligomers may also correlate with the initial symptomatology of the disease⁶.

A is derived from APP by two proteolytic cleavages. APP is first cleaved by -secretase or -site APP-cleaving enzyme (BACE), a membrane-bound aspartyl protease, to generate the N terminus of A within the C-terminal APP membrane-bound fragment of 99 amino acids, termed C99 or -CTF⁷. A second cleavage within the hydrophobic transmembrane domain (TMD) generates and releases A from APP. This enigmatic intramembrane cleavage event, also termed regulated intramembrane proteolysis (RIP)⁸, has been attributed to -secretase. The first molecule associated with -secretase is the remarkable presenilin, first cloned in 1995 through POSITIONAL CLONING strategies in FAD kindreds⁹. The presenilin family now consists of two close members, PS1 and PS2, and more distantly related homologs, one of which is a signal peptidase that removes membrane-associated signal peptides¹⁰. Presenilins are multifunctional proteins spanning several membranes that may function as an aspartyl protease within the catalytic core of the -secretase complex to cleave APP and other substrates¹¹. In addition to presenilin, -secretase requires nicastrin, anterior pharynx defective-1 (Aph-1) and presenilin enhancer-2 (Pen-2)¹². Coexpression of presenilin, Aph-1, Pen-2 and nicastrin, but not any three of these four proteins alone, increases -secretase activity in transfected cells. Moreover, the four proteins together are sufficient to reconstitute -secretase activity in yeast^{13, 14, 15, 16}. What each player in this quartet contributes to the formation of the active -secretase complex is still under investigation. It seems that proper maturation, folding and trafficking of presenilin requires one or more of the other components, but they may or may not be part of the core enzymatic activity. The current evidence favors a model in which presenilin, containing the catalytic aspartate residues of -secretase, is the actual protease¹⁷.

A peptides are heterogeneous. Increasing evidence suggests that A42, the 42–amino acid A isoform, is the pathogenic A species. Both the shorter and more abundant A40, as well as A42, are constitutively produced both in vitro and in vivo. However, A42 aggregates more readily than A40 in vitro, and is consistently more abundant than A40 in the brain¹⁸. A aggregated into oligomers or fibrils are toxic to a variety of cells in culture¹⁹. All genetic mutations that cause FAD affect the substrate (APP) or the protease complex (presenilin) and are consistently associated with selective increase in A42 peptides or total A levels²⁰. Trisomy 21 (Down's syndrome) individuals almost invariably develop classic AD pathology beyond the third decade consistent with increased APP gene dosage and expression. The brains of trisomy 21 individuals show elevated A42 levels, even during gestation²¹. However, a person with partial trisomy 21 that did not encompass the APP and surrounding genes (and thus had only two copies of APP) did not develop AD pathology in late life²², suggesting that an extra copy of the APP gene is crucial for the development of AD pathology in trisomy 21 individuals and, by inference, implicates APP and A in cases of AD. Further support of the latter assertion comes from the observation that the major risk factor for sporadic AD, the 4 allele of APOE²³, is also involved in amyloid deposition. Individuals with AD who have the 4 allele show more amyloid deposits, consistent with the observation that apoE-deficient animals show virtually no A deposits in the brain²⁴. The precise mechanism by which ApoE4 increases AD risk is not clear, but apoE may affect the clearance apparatus for A, alter A aggregation or indirectly affect A by affecting cholesterol metabolism^{24, 25}. In sum, these observations provide some of the strongest evidence supporting the amyloid hypothesis⁴. There are still some concerns, however. The degree of A42 elevation does not correlate with age of onset of the disease in FAD cases, leading many to postulate that presenilin mutations may also contribute to other cellular abnormalities that collectively lead to neurodegeneration. Moreover, the vast majority of AD cases do not carry these presenilin mutations. Consequently, if the amyloid hypothesis were correct, other mechanisms must be in play to affect A accumulation. For example, age-dependent reduction in A clearance or degradation, perhaps a process to which many accumulated insults can contribute, might underlie the pathogenesis of AD in the majority of individuals who do not have mutations in APP or presenilin genes. The remaining discussion therefore evaluates the possibility that mechanisms not related to A, but primarily related to presenilin activity, contribute to sporadic cases of AD.

Shortly after the identification of PS1 and PS2, it became apparent that presenilins also participate in Notch signaling, which is required for all metazoans to specify cell fate and regulate other cellular decisions during development and in adulthood³⁸. Notch proteins are receptors for the Delta–Serrate–Lag2 ligand family acting by short-range contacts between ligand-expressing cells and receptor-expressing cells. The Notch receptors are membrane-bound transcription coactivators that must be released from the cell membrane by -secretase-mediated cleavage to transduce a signal¹⁷. Like APP, an antecedent extracellular membrane cleavage must first take place (- or -secretase for APP, TACE or Kuz for Notch at a site called S2) before intramembrane cleavage can proceed. Ligand binding regulates S2 cleavage by the a disintegrin and metalloproteinase (ADAM) family members; the resultant C-terminal fragment of Notch, termed NEXT for Notch extracellular membrane truncation, is then cleaved within the TMD by the -secretase complex (S3 cleavage) to release the Notch intracellular domain (NICD)³⁹. Once it enters the nucleus, NICD converts CSL DNA-binding proteins (CBF1/RBPjk in vertebrates, suppressor of hairless in Drosophila and Lag-1 in Caenorhabditis elegans) from repressor to a transcriptional activator to allow transcription of target genes.

Several studies point to a possible role for Notch in postmitotic neurons⁴⁷. Activation of Notch in primary hippocampal neurons inhibits neurite extension, and this effect is attenuated in PS1-deficient neurons (or with -secretase inhibitors), indicating that modulation of neurite outgrowth is mediated by NICD. Activation of Notch in neurons with pre-existing neurites led to retraction of these processes^{48, 49}. These effects of Notch can be blocked by expression of Numb, Numb-like and Deltex, which are modulators of Notch signaling in other systems⁴⁹. Notch ligands are present in the brain, and Notch receptors can be detected in the nucleus of maturing and adult neurons⁴⁹. A decline in Notch activity may perhaps underlie a loss of cognitive ability; however, Notch expression is elevated twofold in brains of AD individuals compared with age-matched control individuals⁵⁰. Therefore, although these observations indicate that Notch has a role in the brain beyond the developmental period, it remains to be determined whether perturbations of Notch signaling in the aged brain are pathophysiologically relevant.

Therefore, the obligatory role of presenilin in -secretase cleavage places presenilin in a crucial position in Notch biology; that is, loss of all presenilin alleles results in a complete Notch deficiency in all metazoans tested^{51, 52}. Similar deficiency in Notch cleavage was noted in presenilin-deficient cells in culture³⁸. Unexpectedly, despite their ability to elevate A42, when some FAD mutations are introduced into presenilin-deficient cells, Notch cleavage was not fully reconstituted. Therefore, FAD-associated presenilin mutations could result in partial loss of function with respect to NICD S3 cleavage, which may in turn impair the release of NICD and its nuclear translocation by a small degree^{53, 54, 55, 56}. However, overall A generation is not perturbed by these mutations, and in fact, consistent with all PS-FAD mutations, they behave as gain-of-function mutations to increase A42 levels. This paradoxical increase in A42 generation coupled with partial loss of activity with respect to other substrates of -secretase (including Notch) has been difficult to explain. Presenilin has been proposed to form a dimer at the catalytic core (Fig. 2); therefore, knowledge of which differential cleavages of the substrate at the interface of two presenilin molecules may provide an explanation of these perplexing findings⁵³.

Fig. 2
		Figure 2 | Schematic of the dimer model of presenilin (PS) at the core of the -secretase complex that cleaves various substrates, including Notch and APP.

Notably, one family presenting with frontotemporal dementia and without clinical AD carried an insertional PS1 mutation at codon 352, which when expressed in cells, decreased total A levels⁵⁷. This could suggest that reduced -secretase activity, as reflected by lowered A production, is also associated with overt neurodegeneration, perhaps affecting the full spectrum of presenilin substrates. Confirmation will have to await postmortem examination of the affected individual as well as further evaluation of the properties of this mutant presenilin. Because all affected FAD kindreds are heterozygous, the net reduction in Notch proteolysis due to the mutations' loss of activity may be negligible, perhaps offset by the increase in Notch protein. However, APP (or other substrates) can compete with Notch for -secretase if their cellular concentration exceeds the capacity of the enzyme^{53, 58}. In this scenario, individuals in whom -secretase activity is already compromised may therefore be susceptible to diminished Notch signaling by competition with other -secretase substrates brought about by an overall decline in -secretase activity. In turn, this reduction in -secretase activity may contribute to synaptic dysfunction and perhaps subsequently neurodegeneration. Arguing against a general, age-related decline in -secretase is the observation that individuals with the APP 'Swedish' mutation, which increases BACE-mediated cleavage, produce more A, a situation that would be improbable if -secretase were limiting or already processing its substrates at full capacity⁵⁹. A second argument against this possibility is that heterozygosity for Notch is not associated with AD, as would be predicted if Notch processing were crucial for AD pathology. Thus, if non-A pathways are involved in neurodegeneration, a mechanism involving general inhibition of Notch signaling seems improbable but does not exclude other presenilin-mediated pathways.

Because APP undergoes the same presenilin-dependent intramembrane proteolysis as Notch, the analogy to NICD is too tempting to ignore. AICD or AID, the cognate intracellular C-terminal fragment released by -secretase activity, is unstable, but it can be stabilized by overexpression of the adapter protein Fe65 (refs. 60, 61, 62). Indeed, a transcriptionally active complex consisting of APP (presumably AICD), Fe65 and Tip60 can drive a heterologous nuclear signaling system^{63, 64, 65}. Moreover, the same complex when overexpressed in cells activates at least one candidate gene, KAI1 (ref. 66). Notably, this transcriptional activity can be inhibited by activation of NF-B, thereby providing a mechanism by which this putative signaling pathway can be physiologically modulated⁶⁷. It should be noted, however, that all the evidence that has been presented to date involves artificial overexpression systems of one or more components of this trimeric complex. Therefore, until convincing data are presented with endogenous APP, a physiological role of AICD in signaling remains speculative.

Several physiological functions have been attributed to APP, such as neuronal migration, cell survival, trophic properties and axonal transport cargo receptor^{68, 69}. Deficiency of APP in mice results in a very mild phenotype, including reduced body size and locomotor activity⁷⁰. Loss of APP and its homolog, APLP2, however, show early postnatal lethality without overt morphological changes in the brain^{71, 72}. Some of these physiological roles may require signaling through AICD, but this notion is at present premature. Recent evidence points to two potential roles of AICD. First, AICD was reported to regulate phosphoinositide (PI)-mediated calcium signaling⁷³. In presenilin-deficient cells or following pharmacological inhibition of -secretase, PI-mediated calcium signaling was attenuated. The same defects were noted in APP-deficient cells, but the deficits can be restored by expression of AICD, providing a novel role of APP in signaling that is in part dependent on presenilin activity⁷³. Second, AICD itself may contribute directly to cell death. The C terminus of APP, including C99 and AICD, is known to be neurotoxic, and APP C-terminal fragments have been noted to increase in the presence of the rare APP and presenilin mutations^{74, 75, 76, 77, 78}. The cytotoxicity of APP C-terminal fragments seems to require an intact caspase site within the cytosolic tail^{79, 80}. Therefore, release of the smaller fragment (C31) after caspase cleavage of C99 may result in activation of genes that contribute to cell death in a manner independent of -secretase. Thus, there are at least several different mechanisms whereby APP may contribute to neurotoxicity: via -secretase cleavage to release AICD or via alternative cleavage of the APP C terminus to release other cytotoxic peptides.

Presenilin and other -secretase substrates

Although APP and Notch were the first two -secretase substrates to be discovered, in the past several years a diverse set of molecules, all type I cell surface proteins, have been added to the list of -secretase substrates (Fig. 3). These include Notch ligands Delta and Jagged, apoER2 lipoprotein receptor, ErbB4 receptor tyrosine kinase, CD44 receptor, low-density lipoprotein receptor–related protein (LRP), p75 neurotrophin receptor (p75NTR), nectin-1, deleted in colon cancer (DCC), syndecan-3, and E- and N-cadherins^{81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94}. There is little in common among these molecules except that they are single transmembrane-spanning proteins and most are known to undergo shedding of a large ectodomain fragment, much like APP and Notch. Because the amino acids within the TMDs of these molecules share little homology, this suggests that sequence specificity is not required for -secretase activity⁹⁵. Whether release of the intracellular fragment from the membrane tether, analogous to the cognate NICD, results in a biologically active peptide, has not been established⁹⁶. It is of note that many of these molecules (DCC, ErbB4, Delta, p75NTR) are known to influence neuronal structure and function, as well as being important for nervous system development (Table 1). ErbB4 is a receptor for neuregulins, which are a family of growth factor proteins with EGF-like motifs that are important in heart, mammary gland and nervous system development⁹⁷. In the brain, they promote neuronal migration as well as neuronal and glial differentiation. Similarly, DCC is the receptor for netrins, which are important mediators of axonal growth⁹⁸. p75NTR is a member of the tumor necrosis factor receptor superfamily and, working together with Trk receptors, p75NTRs create high-affinity binding sites for the neurotrophins⁹⁹. Notably, p75NTR has been reported to be a 'receptor' for A, and this binding has been linked to apoptosis¹⁰⁰. In addition, by associating with Nogo receptor, this complex acts as a receptor for axonal growth inhibitors such as Nogo, MAG and OMgp¹⁰¹. In sum, processes crucial in neural development have again been mentioned in the context of presenilin activity. Nevertheless, despite the compelling evidence that these new -secretase substrates are necessary for CNS development and function, the role of TMD cleavage of these proteins is at present unclear.

Fig. 3
		Figure 3 | Schematic showing the type I membrane proteins that are known substrates for -secretase and presenilin.

Table 1
		Table 1 | Molecules regulated by presenilin activity

Some cadherins are -secretase substrates, and their biology presents another possibility for affecting neurodegeneration. It was first shown that E-cadherin is cleaved by -secretase activity not within the TMD but at the membrane-cytoplasm interface⁹⁰. Therefore, presenilin-dependent proteolysis of E-cadherin is not a classical RIP event, nor does the released cadherin fragment translocate into the nucleus. More relevant, however, is the potential involvement of CREB binding protein (CBP) within the -secretase-released substrates. It was first shown that the released ICD of CD44 potentiates transactivation of CBP¹⁰². Recently, N-cadherin was also shown to be a -secretase substrate whose cleavage is stimulated by membrane depolarization. The released C-terminal fragment (N-Cad/CTF2) repressed CREB-dependent activation by accelerating the turnover of CBP⁸⁹. Finally, consistent with the effects of presenilin mutations on NICD release, some PS1 FAD mutations impaired N-cadherin cleavage, thereby releasing the repression of CREB-mediated gene transcription⁸⁹. The observation that expanded polyglutamine repeats in Huntington's disease is also associated with enhanced degradation of CBP suggests that perhaps CBP metabolism contributes to neurodegeneration¹⁰³.

Therefore, these findings indicate that -secretase cleavage of a substrate, in a transmitter-dependent manner, influences transcription of genes related to learning and memory in a mechanism distinct from that used by Notch. In sum, as tempting as it is to postulate that perturbations in the signal transduction mediated by these substrates for presenilin and -secretase affect neuronal function, it is impossible at this time to definitively assign a pathological role for these molecules in neurodegeneration. Even if this is true, the mechanism by which these pathways may be altered in sporadic AD cases is even more mysterious.

Glycogen synthase kinase 3, Wnt signaling and AD?

Recent finding suggest that glycogen synthase kinase 3 (GSK-3) inhibitors can impair the production of A in cultured cells¹⁰⁴. The mechanism for this reduction in A generation is unclear, but it does not seem to be through direct -secretase inhibition. Further studies showed that the GSK-3 isoform may be primarily responsible for the effect; however, GSK-3 cannot be excluded. Moreover, GSK-3 has been shown to interact with PS1, and its activity can be inhibited by some PS1 mutations¹⁰⁵. In this context, it should be noted that GSK-3 has also been postulated to be involved in the abnormal hyperphosphorylation of the microtubule-associated protein, tau¹⁰⁶. It has been proposed that tau hyperphosphorylation is an early event that leads to neurofibrillary tangle formation, the other characteristic pathological hallmark in AD.

Fueling the speculations of a link between Wnt signaling and the two major pathological changes in AD is the observation that PS-1 contributes to regulation of -catenin turnover. -Catenin holds a central position in transducing the signals mediated by Wnt ligands in the so-called canonical Wnt pathway, which, like Notch, is involved in development (including nervous system) and cancer¹⁰⁷. In the canonical pathway, Wnt leads to stabilization of cytosolic -catenin, whereupon -catenin enters the nucleus and associates with LEF/TCF transcription factors to activate Wnt target genes. In the absence of Wnt, -catenin is rapidly phosphorylated by the 'priming' casein kinase-1 (CK1) coupled to the axin complex; this allows GSK-3 to further phosphorylate -catenin, which targets it for degradation by the proteosome¹⁰⁸. Notably, presenilin works in parallel with the axin–CK1 pathway to promote -catenin degradation by acting as a scavenging scaffold to phosphorylate -catenin after priming by a different kinase, possibly protein kinase A¹⁰⁹. This activity is preserved in the presence of an aspartate mutation that normally abrogates -secretase cleavage, suggesting its independence from 'classical' -secretase function. However, it is not known whether Aph-1, Pen-2 and nicastrin are also required. Finally, some PS1 mutations appear to result in stabilization of cytosolic -catenin, potentially causing abnormal activation of Wnt-responsive genes¹¹⁰. How this function of presenilin contributes to AD is unclear at present.

In summary, almost a century has elapsed since Alois Alzheimer described the vivid pathological lesions that characterize this disease. Deciphering the mechanisms of neurodegeneration in AD as well as in other neurodegenerative conditions has not been an easy task. Compelling evidence has shown that presenilin, by regulating intramembrane proteolysis, may be at the hub of several signaling pathways that are active in the adult nervous system. Disease-associated presenilin mutations clearly alter A generation, but in addition, they can also affect neuronal signaling and maintain intracellular calcium stores, protein trafficking and protein turnover. In this article, we speculate on how misregulation of presenilin activity might affect developmentally active pathways, some of which may contribute to neuronal dysfunction. Nevertheless, none of these pathways can currently mount a serious challenge to the amyloid hypothesis as having a primary causal role in neurodegeneration or AD. Definitive evidence is now required to determine whether perturbations in the metabolism of any molecule other than APP can affect neuronal dysfunction or synaptic loss in AD. In the end, the challenge remaining is to explain how the disease begins in late life in the absence of somatic mutations.

Acknowledgements

The authors thank S. Colamarino for reviewing the manuscript and for her suggestions, and M. Mehler for previous discussions. Studies from the authors' laboratories have been supported in part by grants NIH GM 55479 (R.K.), NS 28121 (E.H.K.), AG05131 (E.H.K.), Alzheimer's Association Grant RG991516 (R.K.) and Zenith Award ZEN-01-3050 (R.K.).

Competing interests statement:

The authors declare that they have no competing financial interests.

References

1. Katzman, R. Alzheimer's disease. N. Engl. J. Med. 314, 964−973 (1986).
2. Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572−580 (1991).
3. Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789−791 (2002). | Article |
4. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353−356 (2002). | Article |
5. Terry, R.D. An honorable compromise regarding amyloid in Alzheimer disease. Ann. Neurol. 49, 684 (2001). | Article |
6. Kirkitadze, M.D., Bitan, G. & Teplow, D.B. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res. 69, 567−577 (2002). | Article |
7. Vassar, R. et al. -secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735−741 (1999). | Article |
8. Brown, M.S., Ye, J., Rawson, R.B. & Goldstein, J.L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391−398 (2000). | Article |
9. Rogaev, E.I. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775−778 (1995). | Article |
10. Weihofen, A., Binns, K., Lemberg, M.K., Ashman, K., & Martoglio, B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215−2218 (2002). | Article |
11. Wolfe, M.S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and -secretase activity. Nature 398, 513−517 (1999). | Article |
12. Xia, W. & Wolfe, M.S. Intramembrane proteolysis by presenilin and presenilin-like proteases. J. Cell Sci. 116, 2839−2844 (2003). | Article |
13. Edbauer, D. et al. Reconstitution of -secretase activity. Nat. Cell Biol. 5, 486−488 (2003). | Article |
14. Kimberly, W.T. et al. -Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. USA 100, 6382−6387 (2003). | Article |
15. Takasugi, N. et al. The role of presenilin cofactors in the -secretase complex. Nature 422, 438−441 (2003). | Article |
16. Luo, W.J. et al. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J. Biol. Chem. 278, 7850−7854 (2003). | Article |
17. Selkoe, D. & Kopan, R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26, 565−597 (2003). | Article |
18. Jarrett, J.T., Berger, E.P. & Lansbury, P.T.J. The carboxy terminus of the amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693−4697 (1993).
19. Yankner, B.A. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16, 921−932 (1996). | Article |
20. Murayama, O. et al. Enhancement of amyloid 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci. Lett. 265, 61−63 (1999). | Article |
21. Teller, J.K. et al. Presence of soluble amyloid -peptide precedes amyloid plaque formation in Down's syndrome. Nat. Med. 2, 93−95 (1996).
22. Prasher, V.P. et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann. Neurol. 43, 380−383 (1998).
23. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921−923 (1993).
24. Bales, K.R. et al. Lack of apolipoprotein E dramatically reduces amyloid -peptide deposition. Nat. Genet. 17, 263−264 (1997).
25. DeMattos, R.B. et al. ApoE and clusterin cooperatively Ssuppress A levels and deposition. Evidence that ApoE regulates extracellular A metabolism in vivo. Neuron 41, 193−202 (2004). | Article |
26. Wolozin, B. et al. Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274, 1710−1713 (1996). | Article |
27. Guo, Q. et al. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid -peptide. J. Neurosci. 272, 3590−3598 (1997).
28. Chui, D. et al. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nature 5, 560−564 (1999). | Article |
29. Guo, Q. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat. Med. 5, 101−106 (1999). | Article |
30. Siman, R. et al. Presenilin-1 P264L knock-in mutation: differential effects on A production, amyloid deposition, and neuronal vulnerability. J. Neurosci. 20, 8717−8726 (2000).
31. Saura, C.A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23−36 (2004). | Article |
32. Rozmahel, R. et al. Normal brain development in PS1 hypomorphic mice with markedly reduced -secretase cleavage of APP. Neurobiol. Aging 23, 187−194 (2002). | Article |
33. Leissring, M.A. et al. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793−798 (2000). | Article |
34. Yoo, A.S. et al. Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561−572 (2000). | Article |
35. Mattson, M.P., Chan, S.L. & Camandola, S. Presenilin mutations and calcium signaling defects in the nervous and immune systems. Bioessays 23, 733−744 (2001). | Article |
36. LaFerla, F.M. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat. Rev. Neurosci. 3, 862−872 (2002). | Article |
37. Yang, Y. & Cook, D.G. Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons. Neuroscience 124, 501−505 (2004). | Article |
38. De Strooper, B. et al. A presenilin-1-dependent -secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518−522 (1999). | Article |
39. Mumm, J.S. et al. A ligand-induced extracellular cleavage regulates -secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197−206 (2000). | Article |
40. Artavanis-Tsakonas, S., Rand, M.D. & Lake, R.J. Notch signaling: cell fate control and signal integration in development. Science 284, 770−776 (1999). | Article |
41. Gaiano, N. & Fishell, G. The role of notch in promoting glial and neural stem cell fates. Annu. Rev. Neurosci. 25, 471−490 (2002). | Article |
42. Presente, A., Andres, A. & Nye, J.S. Requirement of Notch in adulthood for neurological function and longevity. NeuroReport 12, 3321−3325 (2001). | Article |
43. Presente, A., Boyles, R.S., Serway, C.N., De Belle, J.S. & Andres, A.J. Notch is required for long-term memory in Drosophila. Proc. Natl. Acad. Sci USA 101, 1764−1768 (2004). | Article |
44. Costa, R.M., Honjo, T. & Silva, A.J. Learning and memory deficits in Notch mutant mice. Curr. Biol. 13, 1348−1354 (2003). | Article |
45. Feng, R. et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 323, 911−926 (2001). | Article |
46. Hitoshi, S. et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 16, 846−858 (2002). | Article |
47. Redmond, L. & Ghosh, A. The role of Notch and Rho GTPase signaling in the control of dendritic development. Curr. Opin. Neurobiol. 11, 111−117 (2001). | Article |
48. Berezovska, O. et al. Notch1 inhibits neurite outgrowth in postmitotic primary neurons. Neuroscience 93, 433−439 (1999). | Article |
49. Sestan, N., Artavanis-Tsakonas, S. & Rakic, P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286, 741−746 (1999). | Article |
50. Berezovska, O., Xia, M.Q. & Hyman, B.T. Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease. J. Neuropathol. Exp. Neurol. 57, 738−745 (1998).
51. Herreman, A. et al. Total inactivation of -secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2, 461−462 (2000). | Article |
52. Donoviel, D.B. et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801−2810 (1999). | Article |
53. Schroeter, E.H. et al. A presenilin dimer at the core of the -secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc. Natl. Acad. Sci. USA 100, 13075−13080 (2003). | Article |
54. Moehlmann, T. et al. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on A 42 production. Proc. Natl. Acad. Sci. USA 99, 8025−8030 (2002). | Article |
55. Song, W., Nadeau, P., Yuan, X., Shen, J. & Yankner, B.A. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl. Acad. Sci. USA 96, 6959−6963 (1999). | Article |
56. Kwok, J.B. et al. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J. Biol. Chem. 278, 6748−6754 (2003). | Article |
57. Amtul, Z. et al. A presenilin 1 mutation associated with familial frontotemporal dementia inhibits -secretase cleavage of APP and notch. Neurobiol. Dis. 9, 269−273 (2002). | Article |
58. Lleo, A. et al. Notch1 competes with the amyloid precursor protein for -secretase and down-regulates presenilin-1 gene expression. J. Biol. Chem. 278, 47370−47375 (2003). | Article |
59. Scheuner, D. et al. Secreted amyloid -protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864−870 (1996).
60. Cupers, P., Orlans, I., Craessaerts, K., Annaert, W. & De Strooper, B. The amyloid precursor protein (APP)-cytoplasmic fragment generated by -secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J. Neurochem. 78, 1168−1178 (2001). | Article |
61. Sastre, M. et al. Presenilin-dependent -secretase processing of -amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2, 835−841 (2001). | Article |
62. Kimberly, W.T., Zheng, J.B., Guenette, S.Y. & Selkoe, D.J. The intracellular domain of the -amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem. 276, 40288−40292 (2001).
63. Cao, X. & Sudhof, T.C. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115−120 (2001). | Article |
64. Scheinfeld, M.H., Ghersi, E., Laky, K., Fowlkes, B.J. & D'Adamio, L. Processing of -amyloid precursor-like protein-1 and -2 by -secretase regulates transcription. J. Biol. Chem. 277, 44195−44201 (2002). | Article |
65. Gao, Y. & Pimplikar, S.W. The -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl. Acad. Sci USA 98, 14979−14984 (2001). | Article |
66. Baek, S.-H. et al. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-B and -amyloid precursor protein. Cell 110, 55−67 (2002). | Article |
67. Zhao, Q. & Lee, F.S. The transcriptional activity of the APP intracellular domain-Fe65 complex is inhibited by activation of the NF-B pathway. Biochemistry 42, 3627−3634 (2003). | Article |
68. Mattson, M.P. Cellular actions of -amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081−1132 (1997).
69. Turner, P.R., O'Connor, K., Tate, W.P. & Abraham, W.C. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog. Neurobiol. 70, 1−32 (2003). | Article |
70. Zheng, H. et al. -amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525−531 (1995). | Article |
71. Heber, S. et al. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20, 7951−7963 (2001).
72. von Koch, C.S. et al. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18, 661−669 (1997). | Article |
73. Leissring, M.A. et al. A physiologic signaling role for the -secretase-derived intracellular fragment of APP. Proc. Natl. Acad. Sci. USA 99, 4697−4702 (2002). | Article |
74. Yankner, B.A. et al. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245, 417−420 (1989).
75. Neve, R.L., McPhie, D.L. & Chen, Y. Alzheimer's disease: a dysfunction of the amyloid precursor protein. Brain Res. 886, 54−66 (2000). | Article |
76. Suh, Y.H. An etiological role of amyloidogenic carboxyl-terminal fragments of the -amyloid precursor protein in Alzheimer's disease. J. Neurochem. 68, 1781−1791 (1997).
77. Passer, B. et al. Generation of an apoptotic intracellular peptide by -secretase cleavage of Alzheimer's amyloid protein precursor. J. Alzheimer's Dis. 2, 289−301 (2000).
78. Hashimoto, Y. et al. The cytoplasmic domain of Alzheimer's amyloid- protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH₂-terminal kinase-mediated neurotoxic signal via dimerization. J. Pharmacol. Exp. Ther. 306, 889−902 (2003). | Article |
79. Lu, D.C. et al. A second cytotoxic proteolytic peptide derived from amyloid -protein precursor. Nat. Med. 6, 397−404 (2000). | Article |
80. Lu, D.C., Shaked, G.M., Masliah, E., Bredesen, D.E. & Koo, E.H. Amyloid protein toxicity mediated by the formation of amyloid- protein precursor complexes. Ann. Neurol. 54, 781−789 (2003). | Article |
81. Ikeuchi, T. & Sisodia, S.S. The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "-secretase" cleavage. J. Biol. Chem. 278, 7751−7754 (2003). | Article |
82. Taniguchi, Y., Kim, S.H. & Sisodia, S.S. Presenilin-dependent "-secretase" processing of deleted in colorectal cancer (DCC). J. Biol. Chem. 278, 30425−30428 (2003). | Article |
83. LaVoie, M.J. & Selkoe, D.J. The Notch ligands, Jagged and Delta, are sequentially processed by -secretase and presenilin/-secretase and release signaling fragments. J. Biol. Chem. 278, 34427−34437 (2003). | Article |
84. Ni, C.Y., Murphy, M.P., Golde, T.E. & Carpenter, G. -secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179−2181 (2001). | Article |
85. Jung, K.M. et al. Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J. Biol. Chem. 278, 42161−42169 (2003). | Article |
86. Kim, D.Y., Ingano, L.A. & Kovacs, D.M. Nectin-1, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/-secretase-like cleavage. J. Biol. Chem. 277, 49976−49981 (2002). | Article |
87. Lee, H.J. et al. Presenilin-dependent -secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277, 6318−6323 (2002). | Article |
88. May, P., Reddy, Y.K. & Herz, J. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J. Biol. Chem. 277, 18736−18743 (2002). | Article |
89. Marambaud, P. et al. A CBP binding transcriptional repressor produced by the PS1/-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114, 635−645 (2003). | Article |
90. Marambaud, P. et al. A presenilin-1/-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948−1956 (2002). | Article |
91. Lammich, S. et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an A-like peptide. J. Biol. Chem. 277, 44754−44759 (2002). | Article |
92. Schulz, J.G. et al. Syndecan 3 intramembrane proteolysis is presenilin/-secretase-dependent and modulates cytosolic signaling. J. Biol. Chem. 278, 48651−48657 (2003). | Article |
93. May, P., Bock, H.H., Nimpf, J. & Herz, J. Differential glycosylation regulates processing of lipoprotein receptors by -secretase. J. Biol. Chem. 278, 37386−37392 (2003). | Article |
94. Murakami, D. et al. Presenilin-dependent -secretase activity mediates the intramembranous cleavage of CD44. Oncogene 22, 1511−1516 (2003). | Article |
95. Struhl, G. & Adachi, A. Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol. Cell 6, 625−636 (2000). | Article |
96. Kopan, R. & Ilagan, X.G. -secretase: proteosome of the membrane? Nat. Rev. Mol. Cell Biol., in press.
97. Crone, S.A. & Lee, K.F. Gene targeting reveals multiple essential functions of the neuregulin signaling system during development of the neuroendocrine and nervous systems. Ann. NY Acad. Sci. 971, 547−553 (2002).
98. Livesey, F.J. Netrins and netrin receptors. Cell Mol. Life Sci. 56, 62−68 (1999). | Article |
99. Chao, M.V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4, 299−309 (2003). | Article |
100. Yaar, M. et al. Binding of -amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. J. Clin. Invest 100, 2333−2340 (1997).
101. Wang, K.C., Kim, J.A., Sivasankaran, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG, and OMgp. Nature 420, 74−78 (2002). | Article |
102. Okamoto, I. et al. Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J. Cell Biol. 155, 755−762 (2001). | Article |
103. Jiang, H., Nucifora, F.C., Jr., Ross, C.A. & DeFranco, D.B. Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum. Mol. Genet. 12, 1−12 (2003). | Article |
104. Phiel, C.J., Wilson, C.A., Lee, V.M. & Klein, P.S. GSK-3_ regulates production of Alzheimer's disease amyloid- peptides. Nature 423, 435−439 (2003). | Article |
105. Takashima, A. et al. Presenilin 1 associates with glycogen synthase kinase-3 and its substrate tau. Proc. Natl. Acad. Sci. USA 95, 9637−9641 (1998). | Article |
106. Lucas, J.J. et al. Decreased nuclear -catenin, tau hyperphosphorylation and neurodegeneration in GSK-3 conditional transgenic mice. EMBO J. 20, 27−39 (2001). | Article |
107. Barker, N., Morin, P.J. & Clevers, H. The yin-yang of TCF/-catenin signaling. Adv. Cancer Res. 77, 1−24 (2000).
108. Liu, C. et al. Control of -catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837−847 (2002). | Article |
109. Kang, D.E. et al. Presenilin couples the paired phosphorylation of -catenin independent of axin: implications for -catenin activation in tumorigenesis. Cell 110, 751−762 (2002). | Article |
110. Soriano, S. et al. Presenilin 1 negatively regulates -catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of -amyloid precursor protein and Notch processing. J. Cell Biol. 152, 785−794 (2001). | Article |
111. Annaert, W.G. et al. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 32, 579−589 (2001). | Article |