Beta amyloid (Abeta) plays a central role in the pathogenesis of Alzheimer's disease. Abeta is the major constituent of senile plaques, but there is a significant presence of Abeta in the brain in soluble forms. The results of functional studies indicate that soluble Abeta interacts with the alpha7 nicotinic acetylcholine receptor (nAChR) complex with apparent high affinity. However, conflicting data exist as to the nature of the Abeta-alpha7 nAChR interaction, and whether it is the result of specific binding. Moreover, both agonist-like and antagonist-like effects have been reported. In particular, agonist-like effects have been observed for presynaptic nAChRs. Here, we demonstrate Abeta(1-42)-evoked stimulatory changes in presynaptic Ca(2+) level via exogenous alpha7 nAChRs expressed in the axonal varicosities of differentiated hybrid neuroblastoma NG108-15 cells as a model, presynaptic system. The Abeta(1-42)-evoked responses were concentration-dependent and were sensitive to the highly selective alpha7 nAChR antagonist alpha-bungarotoxin. Voltage-gated Ca(2+) channels and internal Ca(2+) stores were both involved in Abeta(1-42)-evoked increases in presynaptic Ca(2+) following activation of alpha7 nAChRs. In addition, disruption of lipid rafts by cholesterol depletion led to substantially attenuated responses to Abeta(1-42), whereas responses to nicotine were largely intact. These results directly implicate the nicotinic receptor complex as a target for the agonist-like action of pico- to nanomolar concentrations of soluble Abeta(1-42) on the presynaptic nerve terminal, including the possible involvement of receptor-associated lipid rafts. This interaction probably plays an important neuromodulatory role in synaptic dynamics.
Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.
The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.
Sporadic Alzheimer’s disease, the most common neurodegenerative disorder of aging, is characterized by cerebral plaques and neurofibrillary tangles. Experimental rodents develop plaques but neither tangles nor substantial neurodegeneration under conditions that guarantee Alzheimer’s in humans, suggesting rodents lack critical co-initiation factors. Accumulation of antigen-reactive memory CD8 T cells increases with aging, and was recently revealed as a hallmark of human Alzheimer’s. The impact of this process on disease initiation, however, has not been established because age-related T cell changes are muted in rodents. We developed a mouse model of human-like CD8 T cell aging that promotes antigen-reactive memory CD8 T cell accumulation. Here we show that these “hiT” mice develop all major hallmarks of Alzheimer’s with aging, including tangle-like inclusions and substantial neurodegeneration. Antigen-reactive CD8 T cells analogous to those in hiT mice increased in Alzheimer’s brain, but decreased earlier in blood, where their loss effectively distinguished the Alzheimer’s continuum from aging controls. Our findings establish a clinically relevant mouse model for sporadic Alzheimer’s and show that age-related immune dysfunction critically contributes to its initiation. They also identify useful immune-based targets to track and potentially treat human Alzheimer’s, while validating a model system to examine age-related disease immuno-biology more generally.
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