Thursday, November 21, 2024
11/21/2024
Project Summary The aging brain undergoes fluctuations in neurotransmitters and gene expression, volumetric atrophy, cellular senescence, vascular dysfunction, neuroinflammation, and cognitive deficits. Age also is a risk factor for developing neurodegenerative disorders like Alzheimer's (AD) and Parkinson's diseases (PD). The current primary therapies for AD and PD target transmission of neurotransmitters acetylcholine and dopamine, and neurotransmitter deficiencies are associated with cognitive and motor impairments. Thus, investigating species differences in neurotransmitters is vital to developing effective models of age-related neurological disorders. Nonhuman primates, particularly chimpanzees, are an invaluable resource for aging studies. Like humans, older apes experience mild decline in memory, executive function, and cognitive flexibility, and their brains bear remarkable similarities to elderly humans in gene expression, cerebrovascular dysfunction, and neuroinflammation. Chimpanzees also exhibit the AD hallmarks of amyloid-beta plaques and neurofibrillary tangles in the absence of significant neuronal loss or dementia symptoms. One possibility for the lack of severe cognitive decline in chimpanzees, despite the presence of AD lesions, may be species-specific alterations in neurotransmitters. While prior studies report mild age-related cholinergic and dopaminergic reductions in aged macaque brains, the effect of aging and AD pathology on neurotransmitters in chimpanzees remains unknown. To address this issue, we will investigate neurotransmitter gene expression and protein levels in the chimpanzee brain for age-, sex- and AD pathology-related changes as observed in humans. Utilizing immunohistochemistry, unbiased stereology, and postmortem brain samples from adult and aged chimpanzees previously identified with AD pathology, we will measure neurotransmitter neuron or axon length densities for: dopamine in the dorsal striatum and midbrain; acetylcholine in the dorsal striatum, basal forebrain, and pons; serotonin in the raphe nucleus; and norepinephrine in the locus coeruleus. We also will examine expression of genes involved in the transmission and metabolism of neurotransmitters using bulk RNA sequencing and frozen brain specimens from young and aged chimpanzees with and without AD pathology. To determine if modifications in neurotransmitters correlate with behavioral changes, we will use archival behavioral data. In addition, we will assess longitudinal changes in cognitive functions using an automated touchscreen testing system, motor skill on a tool use task, walking speed, and agonistic and affiliative social interactions in a cohort of living chimpanzees. Distinguishing if species differences in neurotransmitter systems are associated with age-related behavioral changes is essential for improving current models of neurodegenerative and psychiatric disorders, and this proposal will fill a critical gap in our evolutionary knowledge of the influence of aging and AD neuropathology on neurotransmitters in chimpanzees, our closest living ancestor.
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