The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Abstract

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

“…One type of specific target molecule for KChIPs is represented by the presenilins (PS1 and PS2), intracellular membrane-associated proteins (Figure 1B), mutations in which are related to early-onset familial Alzheimer’s disease [45]. The first KChIP to be identified as an interaction partner for both PS1 and PS2 was KChIP3, then dubbed “calsenilin”, because it was able to bind both calcium and presenilin [18].…”

“…KChIP3 (calsenilin) and KChIP4 (CALP), both diffusely distributed in the cytoplasm when expressed alone, were shown to be targeted to intracellular membranes when co-expressed with PS2 [16,18]. Presenilins are part of a multi-protein γ-secretase enzyme complex, which mediates the γ-cleavage of amyloid precursor protein (APP) to produce Aβ peptides, a process which is dysregulated in Alzheimer’s disease [45]. Since KChIP3 (calsenilin) overexpression enhances this γ-secretase activity, it has been suspected that KChIP3 (calsenilin) represents a calcium sensor of the γ-secretase enzyme complex (Figure 1B) [46].…”

Aβ40 promotes neuronal cell fate in neural progenitor cells

“…3,4 The beneficial role of Ab40 is also suggested by studies using PS1 knockout models, which undergo neurodegeneration in the absence of Ab production. 5 In the PS1 exon 10 deletion mice, there are very low levels of Ab40 but accelerated amyloid plaque deposition. 6 A very recent study shows that Ab40 inhibits Ab42-initiated amyloid deposition in vivo.…”

Conditional Deletion of Notch1 and Notch2 Genes in Excitatory Neurons of Postnatal Forebrain Does Not Cause Neurodegeneration or Reduction of Notch mRNAs and Proteins

“…We previously reported that conditional inactivation of PS in excitatory neurons of the cerebral cortex causes progressive memory impairment and age-related neuronal degeneration (36,37), raising the possibility that loss of PS function may underlie dementia and neurodegeneration in AD (38). Furthermore, similar inactivation of nicastrin, another key component of the ␥-secretase complex, also leads to memory impairment and neurodegeneration (39), suggesting that ␥-secretase-dependent activity of PS is important for neuronal survival.…”