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Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

ABSTRACT: Although the cognitive impairment in Alzheimer's disease (AD) is believed to be caused by amyloid-? (A?) plaques and neurofibrillary tangles (NFTs), several postmortem studies have reported cognitive normal subjects with AD brain pathology. As the mechanism underlying these discrepancies has not been clarified, we focused the neuroprotective role of astrocytes. After examining 47 donated brains, we classified brains into 3 groups, no AD pathology with no dementia (N-N), AD pathology with no dementia (AD-N), and AD pathology with dementia (AD-D), which represented 41%, 21%, and 38% of brains, respectively. No differences were found in the accumulation of A? plaques or NFTs in the entorhinal cortex (EC) between AD-N and AD-D. Number of neurons and synaptic density were increased in AD-N compared to those in AD-D. The astrocytes in AD-N possessed longer or thicker processes, while those in AD-D possessed shorter or thinner processes in layer I/II of the EC. Astrocytes in all layers of the EC in AD-N showed enhanced GLT-1 expression in comparison to those in AD-D. Therefore these activated forms of astrocytes with increased GLT-1 expression may exert beneficial roles in preserving cognitive function, even in the presence of A? and NFTs.

SUBMITTER: Kobayashi E

PROVIDER: S-EPMC5786045 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

Kobayashi Eiji E Nakano Masako M Kubota Kenta K Himuro Nobuaki N Mizoguchi Shougo S Chikenji Takako T Otani Miho M Mizue Yuka Y Nagaishi Kanna K Fujimiya Mineko M

Scientific reports 20180126 1

Although the cognitive impairment in Alzheimer's disease (AD) is believed to be caused by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), several postmortem studies have reported cognitive normal subjects with AD brain pathology. As the mechanism underlying these discrepancies has not been clarified, we focused the neuroprotective role of astrocytes. After examining 47 donated brains, we classified brains into 3 groups, no AD pathology with no dementia (N-N), AD pathology with no deme ...[more]

PMID: 29374250

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Project description:Understanding short-term cognitive decline in relation to Alzheimer's neuroimaging biomarkers in early stages of the development of neuropathology and neurodegeneration will inform participant recruitment and monitoring strategies in clinical trials aimed at prevention of cognitive impairment and dementia. We assessed associations among neuroimaging measures of cerebral amyloid pathology, a hallmark Alzheimer's neuropathology, hippocampal atrophy, and prospective cognition among 171 cognitively normal Baltimore Longitudinal Study of Aging participants (baseline age 56-95 years, 48% female, 562 cognitive assessments, 3.7 years follow-up). We categorized each individual based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. To investigate the effects of amyloid dose and degree of hippocampal atrophy, we assessed the associations of continuous mean cortical amyloid level and hippocampal volume with cognitive performance among individuals with detectable amyloid pathology at baseline. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition (A+N- versus A-N-: β = - 0.069, P = 0.017; A-N+ versus A-N-: β = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (β = - 0.123, P = 0.015), visual memory (β = - 0.121, P = 0.036), language (β = - 0.144, P = 0.0004), and mental status (β = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (β = - 0.135, P = 0.004), visual memory (β = - 0.141, P = 0.010), language (β = - 0.108, P = 0.006), and mental status (β = - 0.165, P = 0.022). Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory (β = - 0.139, P = 0.036), language (β = - 0.132, P = 0.005), and mental status (β = - 0.170, P = 0.049). Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Among individuals with amyloidosis, higher baseline amyloid level was associated with lower concurrent visual memory, steeper declines in language, visuospatial ability, and mental status, whereas greater hippocampal atrophy was associated with steeper declines in category fluency. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease according to research criteria. Our findings highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs.

Dataset Information

Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

Publications

Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

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