Neural stem cell-mediated repair of neurodegeneration

肖志成

澳大利亚莫纳士大学

Currently an estimated 26.6 million people suffer from AD worldwide. Fundamental to defining therapeutic targets for AD is to understand the underlying pathogenic mechanisms. In AD, abnormal processing of amyloid precursor protein (APP) leads to accumulation of A peptide and subsequent formation of amyloid plaques. Recently we identified TAG-1 as a novel APP ligand, increasing APP intracellular domain (AICD) release in a-secretase-dependent manner. Importantly, in embryonic neural stem cells (NSCs) this process negatively regulates neurogenesis. We hypothesize that APP-TAG-1 interactions modulate adult NSCs, and particularly those in the aging population under pathological conditions such as AD. The specific aims are to explore: (1) the role of TAG-1/APP pathway in neurogenesis and early AD development; (2) the role of APP in myelination and early AD development; (3) the physiological function of APP in modulating sodium channels: (4) the relationship between physiological nodal distribution of APP and pathological deposition of A during early AD development, and to identify the nodal molecules that regulate A release via modulation of the activity of nodes of Ranvier. APP is a ubiquitous type I membrane protein. APP knockout mice show reduction in brain volume whereas deletion of APP results in developmental lethality and neuroanatomical abnormalities. This suggests a role of APP in neural development. In AD, there is a significant reduction of Musashi1-positive progenitor cells in the SVZ, but an increase in GFAP-negative astrocyte-like cells with progenitor characteristics. APP reduces the neuronal differentiation of stem/progenitor cells. Treatment with a high dose of sAPP, wild-type APP gene transfection and transplantation of human neural stem cells into APP-transgenic mouse brain all increased gliogenesis and reduced neurogenesis in human neural stem cells. In contrast, there is increased hippocampal neurogenesis in AD. Our recent finding (Nature Cell Biology 10:283-294) that TAG-1/APP signaling suppresses neurogenesis in mouse neural stem/progenitor cells may shed light on the mechanisms by which APP modulates stem/progenitor cell functions. Thus it will be important to explore the mechanisms by which this interaction leads to reduction of neurogenesis.