Synaptic function of nicastrin in hippocampal neurons

Abstract

Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

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

“…Furthermore, similar genetic analysis of another γ-secretase component, Nicastrin, confirmed the importance of γ-secretase in memory, synaptic function and neuronal survival (Lee et al, 2014; Tabuchi et al, 2009). In principle, there are two potential explanations for these unexpected in vivo findings: the essential roles played by PS in the maintenance of memory and synaptic function and protection of cortical neurons from neurodegeneration may represent mere coincidence with no relevance to FAD; or alternatively, pathogenic PSEN mutations compromise the essential physiological roles of PS in memory, synaptic function and neuronal survival, leading over time to neurodegeneration and dementia in FAD.…”

Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain

“…While mice don’t mimic all end-stage neuropathological features of the human disease, animal models have proven to be useful tools for the investigation of the pathogenic mechanisms. For example, APP transgenic mice provide excellent models of amyloidosis and offer insight into the consequences of Aβ accumulation and deposition (Ashe and Zahs, 2010), whereas Presenilin and Nicastrin mouse models highlight the importance of γ-secretase in learning and memory, synaptic function and neuronal survival (Lee et al, 2014; Saura et al, 2004; Tabuchi et al, 2009; Wines-Samuelson et al, 2010; Yu et al, 2001; Zhang et al, 2009; Zhang et al, 2010), and offer insight into the pathogenic mechanisms of PSEN1 mutations (Xia et al, 2015). The lack of significant neurodegeneration in mouse brains with massive Aβ accumulation may be interpreted as reflecting the lower potency of Aβ accumulation, relative to loss of Presenilin activity, in causing neurodegeneration.…”

Partial Loss of Presenilin Impairs Age-Dependent Neuronal Survival in the Cerebral Cortex

“…However, in the absence of PS1, PS2 does play essential roles. For example, mice lacking both PS1 and PS2 die much earlier than PS1 KO mice at embryonic day 9 (Shen et al, 1997;Donoviel et al, 1999), and the neurogenesis defects caused by loss of both presenilins in neural progenitor cells are much more severe than those observed in neural progenitor cell-restricted PS1 cKO mice (Shen et al, 1997;Handler et al, 2000;Wines-Samuelson et al, 2005;Kim and Shen, 2008). Similarly, in the adult brain, PS cDKO mice lacking both presenilins in excitatory neurons of the adult cerebral cortex develop striking neurodegeneration and severe memory impairment during aging, whereas PS1 cKO mice exhibit mild memory impairment but no neurodegeneration (Yu et al, 2001;Saura et al, 2004;Wines-Samuelson et al, 2010;Fig.…”