ANTI-AMYLOID BETA THERAPY RESTORES STROKE RECOVERY IN BRAINS WITH ALZHEIMER’S DISEASE PATHOLOGY

Stroke and dementia are representative comorbidities contributing to the increase in disabilities in aging society. However, it remains unclear how cerebral amyloid beta (Aß) accumulation affects the cellular and molecular mechanisms underlying functional recovery after ischemic stroke. We investigated the impact of Aß accumulation on post-stroke recovery process using App^NL-G-F knock-in (KI) mice and human postmortem brain samples. Ischemic stroke in mice was induced by photothrombosis, and neurological deficits were assessed via the cylinder and grid walk tests. Gene expression profiles were analyzed using bulk and single-cell RNA sequencing (scRNA-seq). We discovered that even minimal Aß accumulation suppresses the expression of genes associated with neural repair and significantly impairs neurological recovery in App^NL-G-F KI mice and human Alzheimer's disease patients. scRNA-seq analysis revealed that Aß accumulation induces a unique, malignant myeloid immunity following stroke in App^NL-G-F KI mice. This immune state amplifies inflammatory cascade through TLR2/4 signaling and IL-1ß production, which actively inhibits synapse organization and nervous tissue remodeling. Post-stroke administration of anti-Aß antibody successfully cleared Aß deposits and resolved this pro-inflammatory myeloid response. This intervention restored recovery-associated gene expression and significantly improved functional outcomes in both young and aged App^NL-G-F KI mice. Intracerebral Aß accumulation creates a unique harmful immune environment that impedes neural repair. Our findings indicate that anti-Aß therapy after stroke represents a promising strategy for restoring functional recovery in brains with Aß pathology.