Modeling presenilin-dependent familial Alzheimer's disease: emphasis on presenilin substrate-mediated signaling and synaptic function.

Angèle T Parent,Gopal Thinakaran

doi:10.4061/2010/825918

Angèle T Parent, Gopal Thinakaran

Open Access

https://doi.org/10.4061/2010/825918

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Abstract

Mutations in PSEN genes, which encode presenilin proteins, cause familial early-onset Alzheimer's disease (AD). Transgenic mouse models based on coexpression of familial AD-associated presenilin and amyloid precursor protein variants successfully mimic characteristic pathological features of AD, including plaque formation, synaptic dysfunction, and loss of memory. Presenilins function as the catalytic subunit of γ-secretase, the enzyme that catalyzes intramembraneous proteolysis of amyloid precursor protein to release β-amyloid peptides. Familial AD-associated mutations in presenilins alter the site of γ-secretase cleavage in a manner that increases the generation of longer and highly fibrillogenic β-amyloid peptides. In addition to amyloid precursor protein, γ-secretase catalyzes intramembrane proteolysis of many other substrates known to be important for synaptic function. This paper focuses on how various animal models have enabled us to elucidate the physiological importance of diverse γ-secretase substrates, including amyloid precursor protein and discusses their roles in the context of cellular signaling and synaptic function.

Highlights

Mutations in PSEN1 and PSEN2 genes, which encode polytopic proteins termed presenilin 1 (PS1) and presenilin 2 (PS2), respectively, cause autosomal dominant early-onset familial Alzheimer’s disease (FAD) [1]
We have observed an increase of spontaneous miniature excitatory postsynaptic current in cortical neurons isolated from PSEN1 KO mice [71], while others have reported that expression of mutant PS1 in cultured hippocampal neurons depresses synaptic transmission by reducing the number of synapses [72]
We have shown that the lack of PS function or expression in cortical neurons produced an increase of steady-state levels of CREB and Rac/p21-activated kinase (PAK) cascade activation, which was associated with an increase of spine-like protrusions [91]

Summary

Introduction

Mutations in PSEN1 and PSEN2 genes, which encode polytopic proteins termed presenilin 1 (PS1) and presenilin 2 (PS2), respectively, cause autosomal dominant early-onset familial Alzheimer’s disease (FAD) [1]. Both PS1 and PS2 proteins (PS) share about 63% homology with the highest similarity in the transmembrane domains where most of the FAD-linked mutations are found [2, 3]. It is becoming clear that FAD-linked PS1 variants exhibit partial-loss-ofenzymatic-function observed as diminution of Aβ40 peptide production and defects in the extent of processing certain other transmembrane substrates (reviewed in [40, 41]). This paper discusses findings from various animal models that reveal the role of PS and FAD-linked PS mutations in synapse formation and function

PS Animal Models

PS and Cellular Substrates of Memory

PS and Synapse Formation

PS and Calcium Signaling

Conclusions