Role of BMP Signaling in the Aging Brain R01 AG054429

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Aging is the leading risk factor for developing sporadic Alzheimer’s disease (sAD) suggesting that the aging process is linked to the pathophysiology of the disease. The aging process is highly variable, and some aged individuals develop non-degenerative cognitive impairment while others are resilient. The biological basis of this heterogeneity is unknown. However, aging is associated with biochemical and morphological changes that may shed insight into the both the phenotypic heterogeneity in aging and the age-related susceptibility to AD. In particular, changes in hippocampal structure and connectivity are associated with aging. Among these changes is a decline in neurogenesis in the dentate gyrus (DG) with decreased performance on hippocampus- dependent cognitive tasks. BMP signaling in the brain increases dramatically with age, and we have been exploring the hypothesis that this underlies aging-related changes neurogenesis and cognition. BMP signaling and neurogenesis are also both altered significantly in AD. However, it is unclear whether changes in BMP signaling and in neurogenesis in AD are an exacerbation of the aging process or rather due to unrelated mechanisms. The goal of this proposed supplement is to use both the knowledge and the tools developed as part of our ongoing studies of the role of BMP signaling in the aging brain to define the role of this signaling pathway in the development of AD. Second to age, the human apolipoprotein E (hAPOE) genotype is the strongest known risk factor for sAD. Further, in aging mice, neuronal expression of the ε4 isoform results in neuron loss and impaired learning and memory, and APOE regulates hippocampal neurogenesis. The convergence of the effects of the aging related increase in BMP signaling and of APOE on cognition and on neurogenesis suggest possible interactions between the aging related increase in BMP signaling, APOE genotype, and the development of sAD. Specifically, we hypothesize that the aging related increase in BMP signaling in brain predisposes neurons to the effects of APOE4 and to development of AD, and that that it explains, at least in part, why aging is the greatest risk factor for sAD. We will use the iPSC lines we derived from sAD patients to explore interactions between APOE genotype and BMP signaling on tau phosphorylation, amyloid ß secretion, and neurite preservation, and on neuronal survival after increasing calcium influx in neurons derived from the iPSCs. We also will examine the role of BMP signaling in development of pathology and of behavioral changes in 5XFAD mice.