Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer's disease pathogenesis.
Proceedings of the National Academy of Sciences of the United States of America(2021)
Abstract
The molecular mechanism of Alzheimer's disease (AD) pathogenesis remains obscure. Life and/or environmental events, such as traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH), are proposed exogenous risk factors for AD. BDNF/TrkB, an essential neurotrophic signaling for synaptic plasticity and neuronal survival, are reduced in the aged brain and in AD patients. Here, we show that environmental factors activate C/EBPβ, an inflammatory transcription factor, which subsequently up-regulates δ-secretase that simultaneously cleaves both APP and Tau, triggering AD neuropathological changes. These adverse effects are additively exacerbated in BDNF+/- or TrkB+/- mice. Strikingly, TBI provokes both senile plaque deposit and neurofibrillary tangles (NFT) formation in TrkB+/- mice, associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits. Depletion of C/EBPβ inhibits TBI-induced AD-like pathologies in these mice. Remarkably, amyloid aggregates and NFT are tempospatially distributed in TrkB+/- mice brains after TBI, providing insight into their spreading in the progression of AD-like pathologies. Hence, our study revealed the roles of exogenous (TBI, HFD, and CCH) and endogenous (TrkB/BDNF) risk factors in the onset of AD-associated pathologies.
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