Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive dysfunction. Current knowledge of the processes leading to Alzheimer's disease is still limited, and no effective treatments are available. Alzheimer's disease is characterized by loss of neurons and the abnormal accumulation of amyloid beta into amyloid plaques and hyperphosphorylated tau into neurofibrillary tangles. However, in the vast majority of AD cases there are no obvious alterations in the molecular pathways causing amyloid beta production or tau hyperphosphorylation and it has been difficult to assign them a causal role in sporadic Alzheimer's disease. It is perhaps more likely that other factors trigger these toxic pathways which subsequently lead to neurodegeneration. Age is the major known risk factor for Alzheimer's disease. It is associated with an increase in cellular injury and inflammation and it has been postulated that an age-related reduction in trophic support makes neurons vulnerable to injury and degeneration. TGF-beta1 is an injury response factor and has been implicated in AD pathogenesis. TGF-beta1 levels in AD brains are increased and correlate inversely with the amount of parenchymal amyloid beta deposition but positively with the amount of cerebrovascular amyloid betadeposition. This is consistent with findings in transgenic mice where TGF-beta1 produced by astrocytes reduces the accumulation of parenchymal amyloid beta while the remaining amyloid beta is found in blood vessels. TGF-beta1 has also potent neurotrophic/neuroprotective effects in numerous cell culture and in vivo models of brain injury and mice lacking TGF-beta1 show spontaneous neuronal cell death and neurodegeneration. Our most recent preliminary studies demonstrate that reduced TGF-beta signaling in neurons promotes AD-like disease in mice suggesting that neuronal TGF-beta signaling may be beneficial. ? ? Based on these findings we propose the hypothesis that aging and reduced trophic support to neurons promotes neurodegeneration and sporadic Alzheimer's disease and that neuronal TGF-beta signaling is a critical trophic signal for neurons to age successfully. To test our hypothesis we will determine how lack of neuronal TGF-beta signaling affects survival, APR processing, and tau phosphorylation in cell culture studies and we will use unbiased screens to identify the transcription factors and TGF-beta responsive genes mediating neuroprotection in neurons. We will block neuronal TGF-beta signaling in AD mouse models in vivo before or during active disease to accelerate disease, and we will specifically increase neuronal TGF-beta signaling before or during active disease to ameliorate disease. These in vivo studies will help us to assess the relevance and potential therapeutic implications of our hypothesis and will evaluate the TGF-bet1 signaling pathway as a potential target for the treatment of Alzheimer's disease. ? ? ? ?
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