| First Author | Wu Z | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 25 | PubMed ID | 34140411 |
| Mgi Jnum | J:338510 | Mgi Id | MGI:6718769 |
| Doi | 10.1073/pnas.2100986118 | Citation | Wu Z, et al. (2021) Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 118(25):e2100986118 |
| abstractText | 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/EBPbeta, an inflammatory transcription factor, which subsequently up-regulates delta-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/EBPbeta 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. |
