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Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology.

ABSTRACT: Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein ?2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.

SUBMITTER: Kao PF

PROVIDER: S-EPMC3398703 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology.

Kao Patricia F PF Banigan Meredith G MG Vanderburg Charles R CR McKee Ann C AC Polgar Peter R PR Seshadri Sudha S Delalle Ivana I

Journal of neuropathology and experimental neurology 20120701 7

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression ...[more]

PMID: 22710966

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Project description:ImportanceIndicators of early-life cognitive enrichment (ELCE) have been associated with slower cognitive decline and decreased dementia in late life. However, the mechanisms underlying this association have not been elucidated.ObjectiveTo examine the association of ELCE with late-life Alzheimer disease (AD) and other common dementia-related pathological changes.Design, setting, and participantsThis clinical-pathological community-based cohort study, the Rush Memory and Aging Project, followed up participants before death for a mean (SD) of 7.0 (3.8) years with annual cognitive and clinical assessments. From January 1, 1997, through June 30, 2019, 2044 participants enrolled, of whom 1018 died. Postmortem data were leveraged from 813 participants. Data were analyzed from April 12, 2019, to February 20, 2020.ExposuresFour indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction) were obtained by self-report at the study baseline, from which a composite measure of ELCE was derived.Main outcomes and measuresA continuous global AD pathology score derived from counts of diffuse plaques, neuritic plaques, and neurofibrillary tangles.ResultsThe 813 participants included in the analysis had a mean (SD) age of 90.1 (6.3) years at the time of death, and 562 (69%) were women. In a linear regression model controlled for age at death, sex, and educational level, a higher level of ELCE was associated with a lower global AD pathology score (estimate, -0.057; standard error, 0.022; P = .01). However, ELCE was not associated with any other dementia-related pathological changes. In addition, a higher level of ELCE was associated with less cognitive decline (mean [SD], -0.13 [0.19] units per year; range, -1.74 to 0.85). An indirect effect through AD pathological changes constituted 20% of the association between ELCE and the rate of late-life cognitive decline, and 80% was a direct association.Conclusions and relevanceThese findings suggest that ELCE was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes.

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Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology.

Publications

Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology.

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