Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair
thesisposted on 10.12.2012, 00:00 by Michael P. Demars
Amyloid precursor protein (APP) has been studied extensively in the pathophysiology of Alzheimer’s disease due to the fact that mutations in APP are causative of familial forms of the disease. However, the physiological significance of the protein has yet to be fully elucidated. APP undergoes sequential metabolism through two distinct pathways involving three enzymatic cleavage events via enzymes termed α-, β, and γ-secretase. These cleavage events produce a number of intra- and extra-cellular metabolites that add complexity to the potential physiological function of APP. α-secretase cleavage produces a soluble extracellular metabolite, soluble amyloid precursor protein alpha (sAPPα), that has been previously shown to have trophic characteristics and contain a cysteine-rich growth factor like domain. In the adult brain, neural progenitor cells (NPC) represent a proliferating population of cells that have the ability to form new neurons in discrete regions. These NPC have been shown to have binding sites for sAPP. In Alzheimer’s disease and normal aging, there is a dramatic decline in the adult neurogenesis. We hypothesized that sAPPα is a growth factor for NPC of the adult brain and alterations in the metabolism of APP/sAPPα during normal aging or in Alzheimer’s disease could contribute to stem cell senescence. In this work we show that sAPPα potently stimulates the proliferation of NPC following α-secretase inhibition independently of epidermal growth factor or basic fibroblast growth factor. Further, sAPPα induces phosphorylation of extracellular signal-regulated kinase (Erk) and transcription of genes associated with cell cycle, neurogenesis and energy metabolism. The soluble metabolite derived from the alternative, pathological, cleavage pathway of APP, sAPPβ, shows only slight proliferative qualities in NPC suggesting that alterations in the normal cleavage pattern of APP could underlie neurogenic impairments in Alzheimer’s disease. Finally, we show that sAPP levels decline with age in a manner that correlates with the timing of neurogenic decline and that a single intracerebroventricular injection of sAPPα is sufficient to ameliorate aging-linked deficits in neurogenesis. Taken together, these results suggest that sAPPα is a proliferation factor for NPC of the adult brain whose decline in aging or Alzheimer’s disease could contribute to neurogenic deficits.