Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2007 Jan 9;104(2):403-9.
doi: 10.1073/pnas.0608332104. Epub 2006 Dec 29.

The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism

Jie Shen  1 , Raymond J Kelleher 3rd
Affiliations
Review

The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism

Jie Shen et al. Proc Natl Acad Sci U S A. .

Abstract

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of beta-amyloid (Abeta) peptides, particularly Abeta42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Abeta have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Abeta42 production, they typically reduce Abeta40 generation and impair other PS-dependent activities. Third, gamma-secretase inhibitors can enhance the production of Abeta42 while blocking other gamma-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Abeta42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of gamma-secretase.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The presenilin hypothesis. This diagram depicts the cascade of events leading to neurodegeneration and dementia in AD, as proposed by the presenilin hypothesis. Pathogenic mutations in PS partially impair γ-secretase-dependent and -independent activities through a dominant-negative mechanism. Elevated levels of Aβ, particularly Aβ42, resulting from pathogenic mutations in APP or PS, or in association with sporadic AD, may act to inhibit PS function, mimicking the effect of PS mutations. Because production of Aβ42 is enhanced by partial loss of PS and γ-secretase activity, Aβ42-mediated inhibition may create a vicious cycle leading to progressively greater impairment of PS function. Loss of PS activity results in synaptic dysfunction, such as deficits in synaptic plasticity, and alterations in molecular signaling events, including impairment of NMDA receptor-mediated functions and reduction in CRE-dependent gene expression. Loss of PS function ultimately leads to age-related, progressive neurodegeneration characterized by loss of synapses, dendrites, and neurons; astrogliosis; and tau hyperphosphorylation.
Fig. 2.
Fig. 2.
Loss of PS function in the adult cerebral cortex causes striking neurodegeneration. Coronal sections of control (Left) and PS conditional double knockout (cDKO) (Right) brains at 9 months of age are shown to illustrate the extent of neurodegeneration in PS cDKO mice. Thin lines mark the boundaries of cortical layers and show the thickness of the cerebral cortex. Note the diffuse thinning of the cerebral cortex and underlying hippocampal atrophy. Labels indicate the locations of the neocortex (NCX) and hippocampus (HI).
Fig. 3.
Fig. 3.
γ-Secretase inhibitors mimic the effects of pathogenic PS mutations. The graph depicts schematically the effects of increasing concentrations of γ-secretase inhibitors on Aβ40 and Aβ42 production, based on data from published reports (–41). Similar findings have been reported with inhibitors of different structural classes, assayed in either cell culture systems or partially purified membrane preparations. Three distinct patterns of change in the levels of Aβ40 and Aβ42 production are observed in response to increasing concentrations of γ-secretase, as indicated above the graph: (i) increased Aβ42 and unchanged Aβ40; (ii) increased Aβ42 and decreased Aβ40; and (iii) unchanged or decreased Aβ42 and decreased Aβ40. Pathogenic PS mutations can be classified into similar patterns based on their effect on Aβ42 and Aβ40 (representative mutations are shown for each pattern), with most mutations corresponding to the intermediate pattern. Thus, the impact of PS mutations on γ-secretase activity can be equated with the effects of varying concentrations of an active site-directed γ-secretase inhibitor. Note that the Aβ42/Aβ40 ratio is consistently increased across all concentrations of γ-secretase inhibitor, suggesting that this ratio provides a more reliable index of γ-secretase inhibition than the individual levels of Aβ42 or Aβ40.
Fig. 4.
Fig. 4.
Large numbers of pathogenic PS1 mutations are diffusely distributed throughout the coding sequence. This diagram shows the distribution of the missense, small insertion and deletion mutations in PS1. In addition to the depicted mutations, in-frame deletion of exon 9 has also been reported in FAD. Residues highlighted in red indicate the sites of identified FAD mutations, and the three residues highlighted in green (L113P, G183V, and insR352) indicate the sites of mutations identified in familial FTD. The two aspartates (D257 and D385) implicated as catalytic residues in the active site of γ-secretase are highlighted in yellow. PS endoproteolysis occurs within the protein sequence derived from exon 9.
Fig. 5.
Fig. 5.
Longer forms of Aβ could act as competitive inhibitors of γ-secretase. (A) The diagram shows the APP amino acid sequence surrounding the sites of intramembranous cleavage by γ-secretase and the major Aβ peptides produced. The intramembranous portion of APP is indicated by the shaded region. Cleavage sites are indicated by inverted arrowheads, with the size of the arrowhead denoting the relative frequency of each cleavage site. Under normal circumstances, Aβ40 is the predominant species produced by γ-secretase cleavage, and Aβ peptides of 43, 42, and 38 residues in length are produced in lower amounts. FAD-linked mutations in PS and APP typically enhance the production of Aβ42 and Aβ43. APP residues at which FAD-linked mutations have been identified are highlighted in red. Interestingly, the longer forms of Aβ (Aβ42, Aβ43) retain the major cleavage site for generation of Aβ40. Although they may be capable of interacting with the enzyme active site, these longer forms of Aβ are unlikely to be efficient substrates for cleavage owing to the absence of distal residues, raising the possibility that they may occupy the active site nonproductively after their generation. Thus, Aβ42 and Aβ43 may act as γ-secretase inhibitors, and their increased production in familial and sporadic AD may result in inhibition of γ-secretase. (B) The amino acid sequence of APP surrounding the multiple intramembranous γ-secretase cleavage sites is diagrammed at top, with the cleavage sites designated by asterisks; the length of the corresponding Aβ peptide is indicated above the sequence. The structure of a typical substrate-based γ-secretase inhibitor and the C-terminal sequences of Aβ43 and Aβ42 are shown below. Substrate-based γ-secretase inhibitors are peptide analogs typically derived from the amino acid sequence surrounding the Aβ42 cleavage site. Residues immediately flanking the cleavage site (A*T) are often modified to incorporate hydroxyethyl isostere or difluoroketone moieties, which mimic the transition state intermediate in aspartic protease catalysis. The C-terminal sequences of Aβ43 and Aβ42 resemble substrate-based peptide inhibitors directed against the Aβ38–Aβ40 cleavage sites.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hardy J, Selkoe DJ. Science. 2002;297:353–356. - PubMed
    1. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Ann Neurol. 1991;30:572–580. - PubMed
    1. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT. J Neuropathol Exp Neurol. 1997;56:965–973. - PubMed
    1. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ, III, Kandel ER, Duff K, Kirkwood A, Shen J. Neuron. 2004;42:23–36. - PubMed
    1. Wines-Samuelson M, Shen J. Neuroscientist. 2005;11:441–451. - PubMed

Publication types

MeSH terms

Substances