A mutant <i>PSEN1</i> causes dementia with lewy bodies and variant Alzheimer's disease

Ishikawa, Atsushi; Piao, Yue-Shan; Miyashita, Akinori; Kuwano, Ryozo; Onodera, Osamu; Ohtake, Hiroaki; Suzuki, Michitaka; Nishizawa, Masatoyo; Takahashi, Hitoshi

doi:10.1002/ana.20393

Cited by 91 publications

(76 citation statements)

References 21 publications

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“…Thus, PS1 mutations can cause neurodegeneration and dementia in humans without increasing A␤ production, possibly by imposing a generalized reduction in PS activity. Moreover, PS mutations also occur in families in which early-onset AD is associated with cortical Lewy bodies, which contain ␣-synuclein aggregates (48)(49)(50). Collectively, these observations further suggest that the variable protein aggregates associated with PS mutations do not play an essential role in the pathogenic mechanism leading to neurodegeneration and dementia.…”

Section: Ps Mutations Can Causementioning

confidence: 87%

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

Shen

Kelleher

2007

Proc. Natl. Acad. Sci. U.S.A.

429

358

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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...

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Section: Ps Mutations Can Causementioning

confidence: 87%

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

Shen

Kelleher

2007

Proc. Natl. Acad. Sci. U.S.A.

429

358

View full text Add to dashboard Cite

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“…Snider et al [14] once reported DLB symptoms appearing in PSEN1 gene FS170 mutation. Ishikawa [15] reported a case that the deletion of the 440th position in PSEN1 leads to the loss of threonine, which also appears as DLB. It is not sure why the mutation of gene PSEN1 can lead to symptoms like DLB.…”

Section: Discussionmentioning

confidence: 99%

“…It is not sure why the mutation of gene PSEN1 can lead to symptoms like DLB. Some cases of autopsy [14][15][16] proved that in addition to AD pathological features, Lewy Bodies (LBs) which is the key pathological feature of DLB is also a very frequent coexistent pathologic abnormality in FAD. It can be found wide spread in the brainstem, limbic areas, nigra and neocortex.…”

Section: Discussionmentioning

confidence: 99%

Presenilin 1 Mutation (A431V) Causing Features of Dementia with Lewy Bodies in a Chinese Family of Alzheimer’s Disease

Qiao¹,

Peng²,

Jin³

et al. 2017

J Alzheimers Dis Parkinsonism

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“…It was autopsy proved in patients with the dupAPP mutation [24], p.V272A mutation [84,101], ΔT440 mutation [137] in the PSEN-1 gene and p.A85V mutation [138] in the PSEN-2 gene.…”

Section: Extrapyramidal Sign and Parkinsonismmentioning

confidence: 99%