A deficiency in neurotrophic factor (NF) signaling has been shown to exacerbate environmental risk factors for the development of Alzheimer's disease (AD) pathogenesis in mice, according to a study reported in the June 22, 2021, online edition of the Proceedings of the National Academy of Sciences.

These findings may have important implications for the discovery and development of new, targeted treatments for the currently incurable progressive neurodegenerative disease.

"Although NFs have been studied in neurodegenerative diseases, ours is the first study in which they been thoroughly explored in conjunction with other risk factors in AD pathogenesis," said Keqiang Ye, a professor in the Department of Pathology and Laboratory Medicine at Emory University School of Medicine in Atlanta, Georgia, USA.

Ye led the study, conducted in his laboratory at Emory by first author, Zhourui Wu, who is now a researcher in the Department of Orthopedics at Tongji Hospital Affiliated to Tongji University School of Medicine in Shanghai, China.

The leading cause of dementia worldwide, AD is characterized by abnormalities in amyloid precursor protein (APP), leading to excessive pathological accumulation of beta-amyloid (Abeta) plaque and tau protein neurofibrillary tangles (NFTs) in brain tissue.

Various environmental and/or life factors have been proposed as being exogenous risk factors for AD, including traumatic brain injury (TBI), a high-fat diet and chronic cerebral hypoperfusion.

However, despite extensive research, the molecular mechanisms underlying how such risk factors contribute to development of AD pathogenesis remain obscure.

Previous studies have shown that signaling via BDNF/TrkB (brain-derived neurotrophic receptor and its receptor, tropomyosin receptor kinase B) pathway, which is essential for synaptic plasticity and neuronal survival, is reduced during aging, including in the brains of elderly AD patients.

"While there have been variable results in the literature from different age groups, the consensus is that BDNF is substantially reduced during aging in human brain," said Ye.

Because BDNF/TrkB pathway signaling is reduced during aging, it has been hypothesized that cross-talk between environmental risk factors and BDNF/TrkB deficiency may mediate AD pathologies.

This hypothesis was investigated in the new PNAS study, in which the authors showed that the environmental AD risk factors activated the CCAT/enhancer-binding protein beta (C/EBPbeta), an inflammatory transcription factor.

C/EBPbeta was shown to upregulate the enzyme delta-secretase, which simultaneously cleaved both APP and tau protein, triggering AD neuropathological changes.

"Environmental risks including diabetes, chronic hypoperfusion or lack of sufficient oxygen and blood in the brain, and TBI all elicit inflammation, which triggers C/EBPbeta activation," noted Ye.

These adverse neuropathological changes were then demonstrated to be additively exacerbated in genetically modified BDNF+/- and TrkB+/- mouse models.

"These adverse changes were shown to additively increase AD pathologies and decrease cognitive functions in these mouse models," Ye told BioWorld Science.

"This strongly suggests that maintaining a healthy lifestyle, with reduced diabetes and hypertension and avoidance of brain injury, will delay AD onset, if combined with physical excise to enhance BDNF production."

Indeed, TBI was shown to provoke both senile Abeta plaque deposition and tau NFT formation in TrkB+/- mice, which was associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits.

"To mimic human TBI, we used a controlled cortex impact model to trigger limited brain injury, which elicits focal lesion and chronic neuroinflammation," explained Ye.

"The inflammation was then shown to activate the C/EBPbeta/AEP [asparagine endopeptidase] signaling pathway, which was exacerbated in half of the BDNF- or TrkB-depleted mice," he said.

"Active C/EBPbeta was also shown to increase both APP and Tau expression, which is subsequently cleaved by elevated AEP, leading to senile plaques and tau NFT pathologies."

Moreover, depletion of C/EBPbeta in genetically modified mice inhibited TBI-induced AD-like pathologies in these models. "Depleting C/EBPbeta in their brains was shown to strongly attenuate TBI-induced AD pathologies," Ye said.

Amyloid aggregates and NFTs were found to be tempospatially distributed in TrkB+/- mice brains after TBI, providing important insights into their spread in the progression of AD-like pathologies.

"AD risk factors, combined with deficient BDNF/TrkB neurotrophic activity, temporally triggered AD-like pathologies in genetically modified mice, while AEP inhibition substantially slowed the pathogenesis," said Ye.

This has important treatment connotations, "as conceivably, inhibiting AEP or activating TrkB receptors using a previously reported AEP agonist, BrD-R13, should provide innovative pharmacological intervention," he noted.

In this regard, "we have obtained FDA-approval for a small molecule TrkB agonist called R13-IND and are now initiating a phase I clinical trial, while an optimized small molecular AEP inhibitor will be introduced into the preclinical IND-enabling study later this year."