UC San Diego

Alzheimer's Disease (AD) is characterized by cognitive impairment, progressive neurodegeneration, and formation of amyloid-[Beta] (A[Beta])-containing plaques. These neuropathological features are accompanied by deregulation of signaling cascades such as the cyclin-dependent kinase- 5 (CDK5) pathway. Recent studies have revealed that neurodegeneration in AD is also associated with alterations in hippocampal neurogenesis, which may play a critical role in cognitive impairments and memory loss. The main objectives of this dissertation were to investigate the cellular mechanisms of defective hippocampal neurogenesis in an animal model of AD, and to examine the role of A[beta] and CDK5, downstream targets, and other potential candidate regulators in the mechanisms of defective neurogenesis in AD. To address these aims, in vitro and in vivo studies designed to inhibit CDK5 activity using pharmacological and genetic approaches demonstrated that CDK5 is critical for hippocampal neurogenesis. In an in vitro model of CDK5 hyperactivation, and in the hippocampus of amyloid precursor protein (APP) transgenic (tg) mice, markers of neurogenesis and neurite outgrowth were reduced. I identified the CDK5 substrate collapsin response mediator protein-2 (CRMP2) as a critical regulator of the effects of hyperactive CDK5 on neuronal maturation in AD. CDK5-mediated hyperphosphorylation of CRMP2 contributed to reduced neurite outgrowth by disrupting microtubule polymerization, and this effect could be rescued by down-regulating CDK5 or blocking CRMP2 phoshorylation. In addition to the role of the CDK5 pathway in neurogenesis in AD, other factors may be involved. In this context, defective hippocampal neurogenesis in AD patients and in APP tg mice was accompanied by increased expression levels of bone morphogenetic protein-6 (BMP6). In vitro studies in NPCs showed that Aβ increased BMP6 levels, and that BMP6 treatment reduced proliferation, supporting a role for BMP6 in hippocampal neurogenesis in AD. Lastly, we found that treatment of APP tg mice with a neurotrophic compound (Cerebrolysin) rescued hippocampal neurogenesis, and this effect was associated with down-regulation of the CDK5 signaling pathway. Taken together, these studies demonstrate that the CDK5 and BMP signaling cascades play important roles in adult hippocampal neurogenesis. Future therapeutic approaches could target these molecular pathways to rescue defective neurogenesis in AD