Modulating Amyloid Pathology-Neural Hyperexcitability Crosstalk for Alzheimer's Disease Therapy

Area of Science:

• Neuroscience
• Nanomedicine
• Pharmacology

Background:

• Current Alzheimer's disease (AD) therapies targeting amyloid-beta (Aβ) show limited efficacy.
• Exacerbation of neural hyperexcitability is a key challenge in AD treatment.
• The interplay between Aβ pathology and neuronal network dysfunction is critical.

Purpose of the Study:

• To develop a nanotherapeutic platform, R@AClipo, for codelivering a TREM2 agonist and a glutamate modulator.
• To investigate the efficacy of R@AClipo in addressing both Aβ pathology and neural hyperexcitability in AD models.

Main Methods:

• Designed R@AClipo, a liposomal nanocarrier modified with Angiopep-2 for blood-brain barrier penetration.
• Codelivered COG1410 (TREM2 agonist peptide) and riluzole (glutamate modulator).
• Assessed Aβ clearance, TREM2 expression, glutamate levels, neural activity (fiber photometry), cognitive performance, and toxicity in AD model mice.

Main Results:

• R@AClipo upregulated TREM2, enhanced microglial Aβ clearance, and reduced glutamate accumulation.
• The nanotherapy mitigated neuronal hyperexcitability, independent of riluzole's contribution.
• TREM2-mediated Aβ clearance alone showed a modest reduction in hyperexcitability.
• Cognitive deficits were improved, and neural activity patterns were restored without observed toxicity.

Conclusions:

• R@AClipo offers a dual-action strategy targeting Aβ accumulation and neural hyperexcitability in Alzheimer's disease.
• This approach demonstrates a physiologically compatible method for AD intervention by addressing pathological crosstalk.
• The findings present a promising therapeutic avenue for Alzheimer's disease, improving upon existing antibody-based strategies.