The amyloid precursor protein: A biochemical enigma in brain development, function and disease

Nalivaeva, Natalia N.; Turner, Anthony J.

doi:10.1016/j.febslet.2013.05.010

Cited by 219 publications

(171 citation statements)

References 119 publications

(143 reference statements)

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“…Our data suggest that APP and PSD-95 may also be part of these clusters. These proteins, like ApoER2, are synaptic proteins (31,32,75,76) and may comprise part of a complex of postsynaptic molecules.…”

Section: Discussionmentioning

confidence: 99%

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Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Divekar

Burrell

Lee

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…APP is transmembrane protein also present in synapses (25,31). It undergoes regulated extracellular and intramembranous cleavage to generate the A␤ peptide that accumulates in Alzheimer disease brains (32).…”

mentioning

confidence: 99%

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Divekar

Burrell

Lee

et al. 2014

Journal of Biological Chemistry

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“…First, little is known of the normal functioning of APP [37], which remains a 'current enigma' [93]. Amyloid precursor protein has been implicated in various brain functions including development, learning, memory, and synaptic plasticity, and it may also be secreted as a neuroprotectant [62,93].…”

Section: Problems and Limitations Of The Amyloid Cascade Hypothesismentioning

confidence: 99%

A critical analysis of the ‘amyloid cascade hypothesis’

Armstrong¹

2014

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A b s t r a c t The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving

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“…The biological role of the amyloid precursor protein (APP) and its proteolytic derivatives (A-beta peptide) in normal brain is still uncertain [4]. However, recent data showed that A-beta peptide is an anti-microbial factor [5].…”

Section: Introductionmentioning

confidence: 99%

“…However, these neuropathological alterations are often also present in the brain of elderly without cognitive alterations or AD pathology [3]. Therefore, it is uncertain whether amyloid or other proteinaceous brain depositions might be causatively linked to AD.The biological role of the amyloid precursor protein (APP) and its proteolytic derivatives (A-beta peptide) in normal brain is still uncertain [4]. However, recent data showed that A-beta peptide is an anti-microbial factor [5].…”

mentioning

confidence: 99%

Individual Risk Detection of Developing Cognitive Decline and Dementia in Adults with Down’s Syndrome

Licastro¹,

Porcellini²

2017

Down Syndr Chr Abnorm

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IntroductionAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Prevalence and incidence of this type of dementia is increasing and extensive research has focused on AD pathogenetic mechanisms to find effective preventive procedures and therapeutic drugs. However, no therapy is available. Therefore, focusing upon diverse aspects of the disease in order to discover new therapeutic strategies appears to be relevant for patients. Moreover, new approaches to the disease's pathogenesis may open innovative prevention opportunities for the elderly or other groups of people without manifest cognitive alterations, but with increased risk of developing dementia.Brain amyloid deposits and intra neuronal neurofibrillary tangles (NFTs) have been suggested as inducers of the disease [1,2]. However, these neuropathological alterations are often also present in the brain of elderly without cognitive alterations or AD pathology [3]. Therefore, it is uncertain whether amyloid or other proteinaceous brain depositions might be causatively linked to AD.The biological role of the amyloid precursor protein (APP) and its proteolytic derivatives (A-beta peptide) in normal brain is still uncertain [4]. However, recent data showed that A-beta peptide is an anti-microbial factor [5]. A recent study reported that the A-beta peptide showed an in vitro anti-virus activity [6]. Therefore, A-beta peptides may play multiple roles in human brain and contribute to antimicroorganism responses.As we elsewhere discussed, genetic data from four genome wide association (GWA) studies on AD [7][8][9] suggested that persistent virus infections may be potentially associated with the age related cognitive decline. In fact, this specific genetic signature may predispose to AD by affecting the individual susceptibility to virus infections [7] during the age associated decline of immune competence. Adults with Down's syndrome (DS) o trisomy of chromosome 21show an elevated risk of cognitive decline and dementia with advancing age. The over expression of the APP gene on the chromosome 21 may lead to an early amyloid deposition in DS brains and be a susceptibility factor for AD [10].Middle age people with DS also show increased tangle brain deposition, neuronal loss and neuro-inflammation along with cerebrovascular pathology [10]. All these factors might accelerate brain aging in DS. A dramatic increase in life expectancy, coupled with a significant reduction in early mortality, has led to a substantial increment in the number of DS subjects reaching old age. This demographic picture parallels increased incidence and prevalence of the age related degenerative diseases in persons with DS.Chronic inflammation is associated with the pathogenesis of most chronic degenerative diseases. In fact, a relevant inflammatory component is always associated with AD, autoimmune diseases, diabetes, atherosclerosis, sarcopenia and cancer. It is of interest that increased levels of circulating inflammatory mediators may be secondary to impaired cytokine resp...

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The amyloid precursor protein: A biochemical enigma in brain development, function and disease

Cited by 219 publications

References 119 publications

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

A critical analysis of the ‘amyloid cascade hypothesis’

Individual Risk Detection of Developing Cognitive Decline and Dementia in Adults with Down’s Syndrome

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