DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice

Zhuge, Fen; Zheng, Liujie; Pan, Yuxiang; Ni, Liyang; Fu, Zhengwei; Shi, Junping; Ni, Yinhua

doi:10.1016/j.expneurol.2024.114689

Cited by 5 publications

(1 citation statement)

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“…The categorization of patients according to microglial-mediated, risk factor-induced tissue injury (as compared to other risk factor mechanisms of injury) will increase the likelihood of successful drug development for AD prevention by modulating microglial neurotoxicity and enable patient-tailored preventive therapies. For example, some anti-diabetic medications, such as metformin and dipeptidyl peptidase-4 inhibitors, also possess microglial-modulatory properties [ 47 , 48 ] and may therefore be suitable for risk factor management and neuroprotection by immune modulation.…”

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confidence: 99%

The “Hit and Run” Hypothesis for Alzheimer’s Disease Pathogenesis

Ganz,

Ben-Hur

2024

IJMS

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. Emerging research has challenged the conventional notion of a direct correlation between amyloid deposition and neurodegeneration in AD. Recent studies have suggested that amyloid and Tau deposition act as a central nervous system (CNS) innate immune driver event, inducing chronic microglial activation that increases the susceptibility of the AD brain to the neurotoxicity of infectious insults. Although modifiable risk factors account for up to 50% of AD risk, the mechanisms by which they interact with the core process of misfolded protein deposition and neuroinflammation in AD are unclear and require further investigation. This update introduces a novel perspective, suggesting that modifiable risk factors act as external insults that, akin to infectious agents, cause neurodegeneration by inducing recurrent acute neurotoxic microglial activation. This pathological damage occurs in AD pathology-primed regions, creating a “hit and run” mechanism that leaves no discernible pathological trace of the external insult. This model, highlighting microglia as a pivotal player in risk factor-mediated neurodegeneration, offers a new point of view on the complex associations of modifiable risk factors and proteinopathy in AD pathogenesis, which may act in parallel to the thoroughly studied amyloid-driven Tau pathology, and strengthens the therapeutic rationale of combining immune modulation with tight control of risk factor-driven insults.

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confidence: 99%