Early death in a mouse model of Alzheimer’s disease exacerbated by microglial loss of TAM receptor signaling

• DOI: 10.1073/pnas.2204306119
• Publication Date: 2022-10-03T19:17:41Z
• Authors: Youtong Huang; Greg Lemke
• Keywords: 0303 health sciences; Amyloid beta-Peptides; Polymers; Neurogenesis; Mice, Transgenic; Plaque, Amyloid; Biological Sciences; Protein-Tyrosine Kinases; Ligands; Hippocampus; Amyloid beta-Protein Precursor; Disease Models, Animal; Mice; 03 medical and health sciences; Phagocytosis; Alzheimer Disease; Seizures; Dentate Gyrus; Animals; Microglia

Recurrent seizure is a common comorbidity in early-stage Alzheimer’s disease (AD) and may contribute to AD pathogenesis cognitive decline. Similarly, many mouse models of that overproduce amyloid beta are prone epileptiform seizures result early sudden death. We studied one such model, designated APP/PS1 , found mutation the TAM receptor tyrosine kinase (RTK) Mer or its ligand Gas6 greatly exacerbated Lethality was tied violent appeared initiate dentate gyrus (DG) hippocampus, where plays an essential role microglial phagocytosis both apoptotic newborn cells normally generated during adult neurogenesis. DG neurons excitatory synapses between cornu ammonis field 3 (CA3) hippocampus were increased TAM-deficient mice, premature death neurogenesis these mice coincident. In contrast, incidence lethal deposition dense-core plaques strongly anticorrelated. Together, results argue TAM-mediated sculpts synaptic connectivity seizure-inducing polymers present prior formation plaques.