A Compound Enhancing Lysosomal Function Reduces Tau Pathology, Microglial Reactivity and Rescues Working Memory in...

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) involves multiple pathologies beyond amyloid beta (Aβ), necessitating complementary therapeutic strategies.
• Autophagy, a cellular degradation pathway, is impaired in AD, contributing to toxic protein accumulation.
• A novel natural mitophagy-inducing compound (MIC) was identified as a potential therapeutic agent for AD.

Purpose of the Study:

• To evaluate the therapeutic effects of MIC on AD pathology and cognitive function in a transgenic mouse model.
• To assess the impact of MIC on amyloid beta (Aβ) and phosphorylated tau (pTau) accumulation, neuroinflammation, and cognitive deficits.

Main Methods:

• Aged 3xTgAD mice and non-transgenic (NonTg) controls were fed standard or MIC-supplemented diets.
• Neuropathological changes were assessed via immunohistochemistry for Aβ, pTau, and microglial reactivity.
• Cognitive function was evaluated using the Morris Water Maze (MWM) and Y-maze tests.

Main Results:

• MIC significantly reduced pTau accumulation and microglial reactivity in 3xTgAD mice at 20 months.
• Spatial learning and memory were improved in aged NonTg controls but not in 3xTgAD mice at 15 months.
• Working memory was restored to NonTg levels in younger 8-month-old 3xTgAD mice, indicating an age-dependent effect.

Conclusions:

• MIC shows potential as a modulator of tau pathology and neuroinflammation in Alzheimer's disease.
• As a natural compound, MIC could be used in combination therapy with Aβ-clearing antibodies for a multimodal AD treatment approach.
• This strategy addresses amyloid, tau, and microglia-related pathologies, offering a comprehensive treatment for AD.