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

PNAS, 2021 · DOI: https://doi.org/10.1073/pnas.2100986118 · Published: June 17, 2021

Simple Explanation

This study investigates how environmental risk factors like traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH) contribute to Alzheimer’s disease (AD), especially when combined with reduced neurotrophic signaling. The research focuses on the BDNF/TrkB signaling pathway, crucial for brain health, and how its deficiency interacts with these environmental factors to worsen AD pathologies. The study highlights the role of C/EBPβ, an inflammatory transcription factor, and δ-secretase, an enzyme that cleaves APP and Tau proteins, in triggering AD-related changes under these conditions.

Study Duration

3-6 Months

Participants

BDNF+/-, TrkB+/- mice, and WT littermates; Human TBI and AD patient brains

Evidence Level

Not specified

Key Findings

1
Environmental factors (TBI, HFD, CCH) activate C/EBPβ, upregulating δ-secretase, which cleaves APP and Tau, exacerbating AD neuropathology in BDNF/TrkB-deficient mice.
2
TBI in TrkB+/- mice provokes senile plaque deposits and neurofibrillary tangles, associated with neuroinflammation, neuronal loss, and cognitive deficits; depletion of C/EBPβ inhibits these effects.
3
Amyloid aggregates and NFT in TrkB+/- mice brains after TBI are distributed in a pattern similar to their spreading in AD progression.

Research Summary

The study demonstrates that environmental risk factors exacerbate AD-like pathologies in mice with reduced BDNF/TrkB signaling through the activation of the C/EBPβ/δ-secretase pathway. TBI-treated TrkB+/- mice develop AD-associated pathologies, including senile plaques and neurofibrillary tangles, accompanied by neuroinflammation and cognitive impairment. The research identifies a potential animal model for sporadic AD, as TBI-treated TrkB+/- mice exhibit spatiotemporal distributions of amyloid and tau pathologies similar to those observed in human AD.

Practical Implications

Therapeutic Target Identification

C/EBPβ and δ-secretase represent potential therapeutic targets for preventing or slowing the progression of AD, particularly in individuals with neurotrophic signaling deficiencies.

Risk Factor Management

Managing environmental risk factors such as TBI, diet, and cerebrovascular health may be crucial in reducing the risk of AD, especially for those with genetic predispositions or age-related declines in neurotrophic support.

Diagnostic and Preventative Strategies

Early detection of C/EBPβ activation and δ-secretase upregulation could aid in identifying individuals at higher risk for AD, enabling earlier intervention strategies.

Study Limitations

1
The study primarily uses mouse models, which may not fully replicate the complexity of human AD.
2
The specific mechanisms by which BDNF/TrkB deficiency leads to C/EBPβ activation require further investigation.
3
The study focuses on a limited set of environmental risk factors, and other factors may also contribute to AD pathogenesis.

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