Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways

Rosenthal, Samantha L.; Kamboh, M. Ilyas

doi:10.1007/s40142-014-0034-x

Cited by 136 publications

(132 citation statements)

References 123 publications

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“…Remarkably, six of the susceptibility genes so far recovered from genome-wide association studies in Alzheimer's disease patients are p53 targets in neurons in our study: BIN1/Amph, PICALM/lap, CR1/CG10186, MEF2C/Mef2, SLC24A4/CG1090, and FERMT2/Fit1 (40,41). p53 may therefore play a critical role in regulating genes involved in Alzheimer's disease pathogenesis, correlating with the known up-regulation of p53 in the disorder (35,36).…”

Section: Genetic Validation Of a P53-dependent Pathway Involved Insupporting

confidence: 59%

p53 prevents neurodegeneration by regulating synaptic genes

Merlo¹,

Frost²,

Peng

et al. 2014

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

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DNA damage has been implicated in neurodegenerative disorders, including Alzheimer's disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis, we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration.

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Section: Genetic Validation Of a P53-dependent Pathway Involved Insupporting

confidence: 59%

p53 prevents neurodegeneration by regulating synaptic genes

Merlo¹,

Frost²,

Peng

et al. 2014

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

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“…It has been implicated as a regulator of synapse formation [29], neural plasticity [30], and iron export [31]. Although APP was the first gene identified for early onset familial AD, only recently has a relationship between APP and LOAD been reported [32,33]. These results are in contrast to other studies that have not found associations between LOAD and common [34] or rare [35] APP SNPs.…”

Section: Discussionmentioning

confidence: 99%

Systems biology approach to late‐onset Alzheimer's disease genome‐wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments

Mukherjee

Russell

Carr

et al. 2017

Alzheimer's & Dementia

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Introduction We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer’s disease (LOAD) loci. Methods We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. Discussion Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

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“…For a more extensive coverage of the literature, the interested reader is referred to excellent recent reviews (Holtzman et al, 2012; Kanekiyo et al, 2014; Mahley and Huang, 2012). In addition to APOE , recent large genome-wide association studies have identified over 20 loci that contribute to the risk of sporadic AD (reviewed in (Reitz, 2012; Rosenthal and Kamboh, 2014)). Several loci, such as CLU (clusterin or apoJ) and ABCA7 , are closely involved in the cholesterol metabolism pathway.…”

Section: Genetic Clinical and Experimental Evidence For Protective Ementioning

confidence: 99%

HDL and cognition in neurodegenerative disorders

Hottman

Chernick

Cheng

et al. 2014

Neurobiology of Disease

139

129

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High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.

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Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways

Cited by 136 publications

References 123 publications

p53 prevents neurodegeneration by regulating synaptic genes

p53 prevents neurodegeneration by regulating synaptic genes

Systems biology approach to late‐onset Alzheimer's disease genome‐wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments

HDL and cognition in neurodegenerative disorders

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