Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Abstract

Summary Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1−/− mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.

Protein Quality Control in Health and Disease

“…It is important to note that the amyloid hypothesis has been seriously challenged by studies showing that, in some cases, AD develops as a result of loss of g-secretase activity (BenGedalya et al 2015;Xia et al 2015). Moreover, in many cases, brains of individuals who suffered from AD contain no excess of Ab (Szaruga et al 2015), and transmissibility experiments strongly suggest that different, prion-like Ab strains exist (Meyer-Luehmann et al 2006).…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…In this regard, it will be worth testing whether the Tau DN allele in heterozygosis prevents memory and synaptic deficits in KI mouse models of human dementias characterized by increased APP processing and tauopathy. 41,[49][50][51][52][53][54][55][56][57] Four things are worth noting concerning the alterations of Tau. First, we see an increase in total brain Tau levels in Tau DN/DN mice, even at young age.…”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…However, several studies have implicated that many of the EOFAD mutations actually abolish γ-secretase activity. Indeed, a recent study employed a knockin approach to investigate the effects two EOFAD PSEN1 mutations have on γ-secretase function and found that these mutations abolished γ-secretase activity (Xia et al, 2015). Correspondingly, another recent study investigated 138 distinct EOFAD PSEN1 mutations and found that 90% of these mutants decreased Aβ production (Sun et al, 2017).…”