Reprogramming Neuroinflammation: Mitochondrial Targets and Immune Checkpoint Inhibitors in Alzheimer's Disease.

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Mitochondrial dysfunction and altered microglial phenotypes are key in Alzheimer's disease (AD) pathogenesis.
• These disruptions cause neuroinflammation, synaptic loss, and impaired amyloid/tau clearance.
• Immune checkpoints (PD-1/PD-L1, CTLA-4) regulate neuroimmune balance, with dual roles in CNS and periphery.

Purpose of the Study:

• To review current insights into mitochondrial dysfunction and immune checkpoint signaling in AD.
• To evaluate the translational potential of targeting these pathways, particularly in combination.
• To propose a dual-targeted therapeutic framework for neuroinflammation in AD.

Main Methods:

• Literature review integrating mechanistic insights.
• Analysis of immune checkpoint pathways (PD-1/PD-L1, CTLA-4) in the CNS.
• Evaluation of therapeutic strategies combining immune checkpoint inhibitors (ICIs) and mitochondrial modulators.

Main Results:

• Microglial mitochondrial issues lead to bioenergetic deficits, oxidative stress, and detrimental reactive states.
• CNS-resident immune checkpoints are protective for microglial homeostasis.
• ICIs show potential for modulating microglial responses and amyloid clearance in AD.

Conclusions:

• A dual-targeted approach combining ICIs and mitochondrial modulators offers a promising strategy for AD therapy.
• This framework aims to restore microglial homeostasis and reprogram neuroimmune circuits.
• Further research is needed to validate combinatorial therapies in AD models.