Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.

R Duncan,Peter Koulen,Bob Song

doi:10.3390/ijms19061621

R Duncan, Peter Koulen + Show 1 more

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https://doi.org/10.3390/ijms19061621

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Abstract

A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.

Highlights

Presenilins have long been known to play a role in familial Alzheimer’s disease (AD) pathogenesis [1]
Mutations in amyloid precursor protein (APP) lead to accumulation of amyloid-beta peptides (Aβ), which can be toxic to neural tissue and contribute to AD pathology in the brain [2] with recent studies indicating that the formation of annular protofibrils by Aβ leads to membrane permeabilization and subsequent dysregulation of ion homeostasis [3]
We discuss the role of presenilin 1 (PS1) and presenilin 2 (PS2) in cellular oxidative stress, in protein degradation/autophagy, and in regulating intracellular endoplasmic reticulum (ER) Ca2+ channels (i.e., inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs))

Summary

Introduction

Presenilins have long been known to play a role in familial Alzheimer’s disease (AD) pathogenesis [1]. We discuss the role of PS1 and PS2 in cellular oxidative stress, in protein degradation/autophagy, and in regulating intracellular endoplasmic reticulum (ER) Ca2+ channels (i.e., inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs)) Investigating this involvement of presenilins in Ca2+ signaling results in unique challenges due to the ubiquitous expression of IP3Rs and RyRs by a wide range of cell types in almost every tissue and organ. This challenge represents a unique opportunity for drug target discovery and clinical drug development efforts by taking advantage of recently identified mechanisms that place presenilins at the crossroads of oxidative stress, calcium signaling, and neuronal viability. This led the authors to conclude that an instable lysosomal vesicular ATPase (vATPase) subunit in PS1-deficient cells causes the deficits in lysosomal autophagy [29]

Presenilins and Oxidative Stress

The Role of Presenilins in Proteasome Function and Autophagy

Functions of Presenilins Outside of AD

Findings

Conclusions