Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development

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.

The Interplay between Ca2+ Signaling Pathways and Neurodegeneration

“…In cases of early-onset AD, presenilin 1 mutations alter lysosomal activity, impairing V-ATPase-mediated lysosomal acidification, and perturbing Ca 2+ homeostasis [166]. In cases of familial AD mutations in the APP, presenilin 1 and 2 genes, subsequent Aβ accumulation was reported [167], and, in embryonic fibroblasts from presenilin-double knockout mice, TPC1 and TPC2 expression levels were altered, and lysosomal Ca 2+ concentrations were reduced [168]. Therefore, it appears as though presenilin is involved in TPC regulation (Table 1).…”

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

“…Mechanistically, these data can be explained by the direct decrease in the production Ab 42 as previously described [45,46]. Alternately, reports showing beneficial changes on synapse function by disrupting g-secretase activity may occur via processing of other substrates involved in synaptic function [47][48][49][50]. Further studies to define a possible role of NGP 555 acting on additional known substrates processed by g-secretase to exert changes in synaptic function are warranted.…”

Electro‐Stimulation, a Promising Therapeutic Treatment Modality for Tissue Repair: Emerging Roles of Sulfated Glycosaminoglycans as Electro‐Regulatory Mediators of Intrinsic Repair Processes

“…[ 80 ] Presenelin 1 and 2 (PS1 and 2) have been suggested as therapeutic targets in the treatment of familial AD. [ 81 ] The functional importance of the regulation of Ca2+ signaling by PS1 and PS2 in AD is impacted by presenilin gene mutation, [ 82 ] drugs that target PS1 and 2 activity thus show therapeutic potential in the treatment of AD.…”