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Author Notes:

Liming Cheng, Email: limingcheng@tongji.edu.cn OR Keqiang Ye, Email: kye@emory.edu

K.Y. designed research; Z.W., C.C., S.S.K., X.L., X.G., and S.P.Y. performed research; C.D.K. contributed new reagents/analytic tools; Z.W., X.G., S.P.Y., L.C., and K.Y. analyzed data; and C.D.K. and K.Y. wrote the paper.

We thank the University of Washington ADRC (NIH Grant No. P50AG005136) and the Kaiser Permanente Adult Changes in Thought Study (NIH Grant No. U01 AG006781) research subjects and their families for brain donation, a tremendous gift to science. We thank Ms. Allison Beller for coordination of tissue requests, subject selection, and tissue transfer and Ms. Kim Howard for histological support.

The authors declare no competing interest.

Subject:

Research Funding:

University of Washington ADRC (NIH Grant No. P50AG005136), (NIH Grant No. U01 AG006781)

This study was supported in part by the Rodent Behavioral Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience National Institute of Neurological Disorders and Stroke (NINDS) Core Facilities (Grant No. P30NS055077).

Further support was provided by the Georgia Clinical & Translational Science Alliance of the NIH under Award No. UL1TR002378. This work is supported by a grant from the NIH (RF1, Grant No. AG051538; RO1, Grant No. NS105982), and the ADRC center grant (P30, Grant No. AG066511) to K.Y., the Funds for International Cooperation and Exchange of the National Natural Science Foundation of China (NSFC) (Grant No. 81810001048), the National Basic Research Program of China (Grant No. 2016YFA0100800) to L.C., Shanghai Pujiang Program (Grant No. 19PJ1409200), and the National Natural Science Foundation of China (Grant No. 82071370) to Z.W. C.D.K. was supported by the Nancy and Buster Alvord Endowment

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • sporadic Alzheimer's disease
  • C/EBP beta
  • delta-secretase
  • risk factors
  • AEP
  • GROWTH-FACTOR EXPRESSION
  • C/EBP-BETA
  • DELTA-SECRETASE
  • SEVERE OBESITY
  • BRAIN INSULIN
  • AXONAL INJURY
  • MOUSE MODEL
  • HEAD-INJURY
  • MEMORY LOSS
  • BDNF

Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer's disease pathogenesis

Tools:

Journal Title:

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume:

Volume 118, Number 25

Publisher:

Type of Work:

Article | Final Publisher PDF

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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