A brain proteomic signature of incipient Alzheimer’s disease in young<i>APOE</i>ε4 carriers identifies novel drug targets

Roberts, J; Varma, Vijay R.; An, Yang; Varma, Sudhir; Candia, Julián; Fantoni, Giovanna; Tiwari, Vinod; Anerillas, Carlos; Williamson, Andrew; Saito, Atsushi; Loeffler, Tina; Schilcher, Irene; Moaddel, Ruin; Khadeer, Mohammed; Lovett, Jacqueline; Tanaka, Toshiko; Pletniková, Olga; Troncoso, Juan C.; Bennett, David A.; Albert, Marilyn; Yu, Kaiwen; Niu, Mingming; Haroutunian, Vahram; Zhang, Bin; Peng, Junmin; Croteau, Deborah L.; Resnick, Susan M.; Gorospe, Myriam; Bohr, Vilhelm A.; Ferrucci, Luigi; Thambisetty, Madhav

doi:10.1126/sciadv.abi8178

Cited by 37 publications

(37 citation statements)

References 165 publications

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“…However, they also have been directly implicated in brain aging phenotypes and neurodegeneration. A recent proteomic analysis also showed differential abundance of protein tyrosine kinases in the ROSMAP brain study between APOE ε4 carriers and non-carriers, and implicated these as key candidates for molecular intervention in incipient AD [ 68 ]. Gated ion channels are of clear physiological relevance to the brain—however, recent evidence further suggests that reduced neural activation may protect the aging brain [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease

Thrush

Bennett

Gaiteri

et al. 2022

Aging

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Alzheimer’s disease (AD) risk increases exponentially with age and is associated with multiple molecular hallmarks of aging, one of which is epigenetic alterations. Epigenetic age predictors based on 5’ cytosine methylation (DNAm), or epigenetic clocks, have previously suggested that epigenetic age acceleration may occur in AD brain tissue. Epigenetic clocks are promising tools for the quantification of biological aging, yet we hypothesize that investigation of brain aging in AD will be assisted by the development of brain-specific epigenetic clocks. Therefore, we generated a novel age predictor termed PCBrainAge that was trained solely in cortical samples. This predictor utilizes a combination of principal components analysis and regularized regression, which reduces technical noise and greatly improves test-retest reliability. To characterize the scope of PCBrainAge’s utility, we generated DNAm data from multiple brain regions in a sample from the Religious Orders Study and Rush Memory and Aging Project. PCBrainAge captures meaningful heterogeneity of aging: Its acceleration demonstrates stronger associations with clinical AD dementia, pathologic AD, and APOE ε4 carrier status compared to extant epigenetic age predictors. It further does so across multiple cortical and subcortical regions. Overall, PCBrainAge’s increased reliability and specificity makes it a particularly promising tool for investigating heterogeneity in brain aging, as well as epigenetic alterations underlying AD risk and resilience.

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Section: Discussionmentioning

confidence: 99%

Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease

Thrush

Bennett

Gaiteri

et al. 2022

Aging

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“…There is some intriguing data derived from human biomaterials that show APOE activates the ERK1/2 MAP kinases via dual leucine-zipper kinase (DLK) [ 47 ]. Another report investigated proteomic profile of young APOE4 carriers where several kinases related to tau phosphorylation, such as atypical protein kinase C (aPKC) PKC-ι, mitogen-activated protein kinase 12 (MAPK12), a member of the p38 MAPK family, Src family tyrosine kinases FYN, and Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) were identified [ 48 ]. Taken together, a gap in our knowledge remains whether APOE is functionally related to cellular metabolism that influences tau phosphorylation or facilitates intercellular transfer of tau or both in AD and related dementias.…”

Section: Discussionmentioning

confidence: 99%

Impact of APOE genotype on prion-type propagation of tauopathy

Williams

Ruiz

et al. 2022

acta neuropathol commun

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Apolipoprotein (APOE) is a major risk factor of Alzheimer’s disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along neuroanatomic connections following a prion-like mechanism. To provide insights into whether APOE isoforms differentially regulate the prion properties of tau and determine trans-synaptic transmission of tauopathy, we have generated human P301S mutant tau transgenic mice (PS19) that carry human APOE (APOE2, APOE3 or APOE4) or mouse Apoe allele. Mice received intrahippocamal injections of preformed aggregates of K18-tau at young ages, which were analyzed 5 months post-inoculation. Compared to the parental PS19 mice with mouse Apoe alleles, PS19 mice expressing human APOE alleles generally responded to K18-tau seeding with more intense AT8 immunoreactive phosphorylated tau athology. APOE3 homozygous mice accumulated higher levels of AT8-reactive ptau and microgliosis relative to APOE2 or APOE4 homozygotes (E3 > E4~2). PS19 mice that were heterozygous for APOE3 showed similar results, albeit to a lesser degree. In the timeframe of our investigation, we did not observe significant induction of argentophilic or MC1-reactive neurofibrillary tau tangle in PS19 mice homozygous for human APOE. To our knowledge, this is the first comprehensive study in rodent models that provides neuropathological insights into the dose-dependent effect of APOE isoforms on phosphorylated tau pathology induced by recombinant tau prions.

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“…Green: The CELF1 locus was associated with AD in genome-wide association studies (Ref. [3][4][5][6]. Red: Transcriptomic studies using CELF1 knockdown revealed strong regulation of KLC1 by CELF1; cross-linking and immunoprecipitation sequencing identified KLC1 RNA as a binding partner of the CELF1 protein and revealed its binding site.…”

Section: Fig 6 Hypothesis-free Omics Approaches Identified a Molecula...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…As a result, there has been precipitous increase in the number of associated loci and genes identified whose function in disease is unknown 1 . Many researchers have suggested that the innovative use of functional omics will be crucial to interpret GWAS results and reveal molecular pathways in complex diseases in the post-GWAS era, but concrete strategies are still being explored 1,2,3,4 . In Alzheimer's disease (AD), there is a sharp disparity between the criticality of the disease, including the large number of patients and the burden of care, and the availability of treatments.…”

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confidence: 99%

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An Alzheimer’s disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

Kikuchi

Viet

Nagata

et al. 2022

Preprint

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In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimer's disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we unexpectedly found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E (KLC1_vE), an amyloid- β (A β) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for A β accumulation confirmed that Klc1_vE drives A β pathology. Using omics methods, we revealed the molecular pathway of a complex disease supported by human and mouse genetics.

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A brain proteomic signature of incipient Alzheimer’s disease in youngAPOEε4 carriers identifies novel drug targets

Abstract: Brain proteins altered in young APOE ε4 carriers are found decades later in Alzheimer’s disease and present novel drug targets.

Cited by 37 publications

References 165 publications

Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease

Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease

Impact of APOE genotype on prion-type propagation of tauopathy

An Alzheimer’s disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

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