LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.

Leucine-rich repeat kinase 2 (LRRK2), primarily expressed in microglia, is responsible for the modulation of innate immune responses and associated with various immunological disorders. Available evidence documents that though as the predominant etiological factor for familial Parkinson's disease, LRRK2 mutations rarely occur in Alzheimer's disease (AD) and that LRRK2 polymorphism is potentially associated with late-onset AD. However, the role of LRRK2 in AD immunopathogenesis remains unknown. In this study, we investigated the impact of LRRK2 deficiency on cognitive function, Aβ plaque accumulation, and plaque-associated neuropathology in AD mice. The results revealed that compared with the 5xFAD mice, the 8-month-old 5xFAD;LRRK2-/- mice reported improved learning and memory, reduced cerebral and hippocampal Aβ plaque burden, and decreased microglia and astrocytes within the central region of hippocampal Aβ plaques. The 5xFAD;LRRK2-/- mice also showed a decrease in several complement and proinflammatory cytokines in the brain, indicating an altered microglial phenotype. Furthermore, the absence of LRRK2 prevented synaptic loss and restored the disrupted equilibrium between excitatory and inhibitory synapses in the 5xFAD mice. These findings suggest that LRRK2 may play an essential role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brain of the 5xFAD mice and that a genomic transgene-blockade of LRRK2 may reprogram the microglial responsivity, thus mitigating the neuropathological and behavioral deficits in AD mice. The 5xFAD;LRRK2-/- mice reduced cognitive impairment in the Morris water maze test compared with the 5xFAD mice. The protective effect of LRRK2 inhibition is not dependent on the APP production process or Aβ degradation. Conversely, 5xFAD;LRRK2-/- mice enhanced microglial phagocytosis, reducing Aβ aggregation and glial activation. Additionally, compared with the 5xFAD, the 5xFAD;LRRK2-/- mice exhibited preserved synaptic structure, characterized by higher PSD95 expression, lower C1qa/C3 expression in both excitatory and inhibitory synapses, upregulated VGLUT1 expression, and downregulated VGAT expression.