AGE-RELATED NETWORK DYSFUNCTION: CONTRIBUTIONS OF NEURAL ACTIVITY TO RISK FOR LATE-ONSET AD

Abstract

This presentation will focus on an age-related shift in neural activity in key circuits that could contribute to boosting progression of Alzheimer's pathology and illuminate the risk conferred by aging in late onset sporadic AD. Neural hyperactivity in aging is associated with memory impairment in outbred rats and non-human primates. Hyperactive hippocampal neurons in those species are similarly localized to increased activation detected by high resolution functional magnetic resonance imaging (fMRI) in elderly humans, a condition that is further augmented in patients with mild cognitive impairment. In addition to the effects of aging on hippocampal circuits, reciprocally connected cortical networks demonstrate alterations in both aging and in prodromal AD. In particular, posterior regions of the default mode network (DMN) that are sites of early amyloid deposition show impaired task-related deactivation in older adults. Studies of the homologous connectional anatomy across species could provide information about the condition of such networks in aging, independent AD pathology. Activation of neural activity was monitored by expression of the immediate early gene cFos to map heightened excitability in behaviorally characterized aged rats. Induction of neural activity was assessed by cFos mRNA expression using quantitative in situ hybridization. Consistent with neurophysiological recording data, greater cFos induction was localized in the hippocampus of aged memory impaired rats compared to unimpaired aged cohorts and young adults. Similar increased cFos was observed in a network of cortical sites, including retrosplenial and parietal regions of the posterior DMN. Pharmacological treatment that reduced excess cFos induction in the hippocampus also normalized cFos induction in posterior DMN. Reduction of neural activity reduces amyloid deposition and preserves synaptic function in AD mouse models. In tau mouse models, manipulation of neural activity also controls tau propagation and pathology in the medial temporal lobe/hippocampus. Heightened neural activity as a condition associated with aging may contribute to the risk conferred by aging in driving the pathophysiology of late-onset sporadic AD. A demonstrated translation for the efficacy of targeting hippocampal hyperactivity in clinical investigations may extend to the additional cortical components of an AD vulnerable network in patients.