Genetics of dementia

Loy, Clement T.; Schofield, Peter R.; Turner, Anne; Kwok, John B.

doi:10.1016/s0140-6736(13)60630-3

Cited by 277 publications

(217 citation statements)

References 135 publications

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“…Genetic evidence strongly supports a causal role for Aβ42 as the triggering event in AD (2). Although the initial amyloid cascade hypothesis posited that the accumulation of Aβ42 into insoluble amyloid fibers was the key triggering event, growing evidence indicates that soluble preamyloid structures are the main contributors to AD pathogenesis (3).…”

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confidence: 99%

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Fernández-Fúnez

Sanchez-Garcia

Mena

et al. 2016

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

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Alzheimer’s disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

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confidence: 99%

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Fernández-Fúnez

Sanchez-Garcia

Mena

et al. 2016

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

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“…For example, those with the E4/E4 genotype are eight times more likely to develop AD than those with the most common E3/E3 genotype, although 50% of those with AD do not carry an E4 allele. 87 Given the pathological association between NFT, Aβ and PDD, 40 there has been interest in the influence of APOE in PD cognitive impairment and meta-analysis found an increased odds ratio of 1.6 for dementia development in those with at least one E4 allele. 88 However, the authors comment that publication bias, study heterogeneity and relatively small numbers (295 PD and 163 PDD) need to be considered when interpreting these data.…”

Section: Sporadic Pdmentioning

confidence: 99%

Cognitive deficits in Parkinson’s disease: current perspectives

Cosgrove¹,

Alty²

2018

JPRLS

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“…MAPT mutation screening therefore may be considered in athletes presenting with presenile onset of behavioral disturbances and parkinsonism. Likewise, as the frequency of presenilin-1 (PSEN1) mutation (the most common pathogenic mutation in AD) increases with early onset dementia and strength of family history, 50,80 autosomal dominant AD may be considered in middle-aged athletes presenting with dementia and possible family history. The occasional cases in the DP literature with middle age onset dementia and frank AD pathology, 5 for example, suggest early onset AD rather than DP.…”

Section: Genetic Predisposition To Chronic Neurodegeneration In Profementioning

confidence: 99%

Chronic traumatic encephalopathy: A paradigm in search of evidence?

Castellani

2015

Laboratory Investigation

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Chronic traumatic encephalopathy (CTE) has been in the medical literature since the 1920s. It is characterized clinically by diverse neuropsychiatric symptoms, and pathologically by variable degrees of phosphorylated tau accumulation in the brain. The evolving paradigm for the pathogenesis of CTE suggests that concussion or subconcussion from athletic participation initiates a cascade of pathologic events, encompassing neuroinflammation and protein templating with trans-synaptic neurotoxicity. The end result is neurologic and neurobehavioral deterioration, often with self-harm. Although these concepts warrant further investigation, the available evidence permits no conclusions as regards the pathogenesis of the reported findings. Investigations into the role of premorbid or co-morbid neurodegenerative diseases has been limited to date, and in-depth genetic analyses have not been performed. The role of concussion or subconcussion if any, whether and how the condition progresses over time, the extent of phosphorylated tau in clinically normal athletes, the role of phosphorylated tau as a toxic species versus an inert disease response, and whether protein templating has any in vivo relevance remain to be elucidated.

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Genetics of dementia

Cited by 277 publications

References 135 publications

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Cognitive deficits in Parkinson’s disease: current perspectives

Chronic traumatic encephalopathy: A paradigm in search of evidence?

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Genetics of dementia

Cited by 277 publications

References 135 publications

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Cognitive deficits in Parkinson&rsquo;s disease: current perspectives

Chronic traumatic encephalopathy: A paradigm in search of evidence?

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Product

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Cognitive deficits in Parkinson’s disease: current perspectives