Deficiency in neuronal TGF-β signaling promotes neurodegeneratbn and Alzheimer's pathology

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the P-amyloid peptide (A beta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (T beta RII) is mainly expressed by neurons, and that T beta RII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted A beta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted A beta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.