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Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults
Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During...
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Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing
Exercise's protective effects in Alzheimer's disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise...
Mitochondrial fumarate inhibits Parkin-mediated mitophagy
Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby...
A role for microglia in mediating the microbiota-gut-brain axis
Microglia, the resident immune cells of the brain, are now recognized as being active participants in the onset and progression of many neurological and neuropsychiatric disorders. As a result, substantial effort has been made in finding ways to target, deplete or modulate the aberrant phenotypes of the microglia that are present in these different disease states, albeit with varied levels of success. The gut microbiota has recently emerged as a master regulator of microglia throughout the...
Aging alters the response to CAR T cell therapy
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