Neurobiology of Aging最新文献

Alzheimer's disease (AD) pathology disrupts functional brain connectivity long before symptoms emerge. African Americans face elevated AD risk, yet underlying mechanisms remain unclear. Genetic risk differs by ancestry: APOE-ε4 strongly predicts late-onset AD in European ancestry, whereas ABCA7 rs115550680 confers substantial risk in African ancestry. Yet, how these variants influence neural function in African Americans is unclear. The medial temporal lobe (MTL) is an early target of AD pathology and resting-state functional Magnetic Resonance Imaging (rs-fMRI) measures of dynamic network connectivity (hereafter "flexibility"), the brain's capacity to dynamically reconfigure connectivity, provide a sensitive metric of network adaptability, potentially preceding structural decline. However, comparative influence of APOE-ε4 and ABCA7 rs115550680 on MTL flexibility and subregional volumes in this population is unknown. 146 older African Americans (Mean_Age=69.71 Mean_SD=6.29) were genotyped for APOE-ε4 and ABCA7 rs115550680 via saliva samples. Rs-fMRI was used to calculate MTL flexibility and T1-weighted MRI quantified MTL subregional volumes. ANCOVAs controlled for age, sex, and education, and APOE-ε4 when ABCA7 rs115550680 was the predictor. ABCA7 rs115550680 risk allele carriers exhibited lower MTL flexibility than non-carriers (p = .042) and APOE-ε4 allele carriers (p = .030). They also showed hypertrophy in left anterior hippocampus (p = .049), bilateral entorhinal cortex (ERC) (right p = .048; left p = .020) compared to non-carriers, and greater left ERC volume than APOE-ε4 allele carriers (p = .027). APOE-ε4 or interaction effects were not significant (p > .05). These findings provide preliminary evidence that ABCA7 rs115550680 risk allele, but not APOE-ε4 allele, is linked to reduced MTL flexibility and subregional hypertrophy in older African Americans, suggesting ancestry-specific mechanisms of early AD risk.

Vestibular dysfunction becomes increasingly prevalent with aging and it is estimated that more than 80 % of people over 80 years old experience balance problems linked to vestibular dysfunction. Within the peripheral vestibular organs, sensory hair cells transform hair bundle motion into receptor potentials and information is next relayed to the brain by electrical activity in vestibular afferent nerves. There are three types of vestibular afferents: calyx-only afferents innervate one or more type I hair cells; bouton dendrites innervate type II hair cells and dimorphic afferents contact both hair cell types. Calyx-only afferents are found solely in central areas of vestibular neuroepithelia and have distinct physiological characteristics. Previous studies have shown changes in vestibular-mediated responses with aging in addition to age-related degeneration of afferent synapses in rodent inner ear epithelia. However, whether calyx-only afferent synapses are lost with aging in vestibular epithelia remains unresolved. Here we used an antibody to the Ca^2 + -binding protein calretinin as a marker of calyx-only afferent terminals in gerbil vestibular epithelia at different ages. We used fluorescent immunohistochemistry and confocal imaging to identify afferent neurons in the utricle and cristae of young (1-2 months), adult (1-2 years), and older adult (≥3 years) gerbils. Counts were made of single, double and triple calretinin-positive calyx terminals in central regions of vestibular epithelia. Overall, a mild decrease in numbers occurred with aging between adult and older adult animals suggesting that aging-related decline in vestibular function can be linked to partial loss of calretinin-positive calyx-only afferent terminals.

Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.