Neuroimmune and Sex-Associated Behavioral Alterations in a Hippocampal α-Synuclein Mouse Model of Lewy Body Dementia

Abstract Lewy body dementias (LBDs) are characterized by α-synuclein (α-syn) aggregation, cognitive impairment, and neuropsychiatric symptoms. Associated neuroimmune and behavioral changes remain incompletely characterized in experimental models across sexes and time points. Male and female mice received hippocampal injections of α-syn preformed fibrils (PFFs) or monomers. Outcomes were assessed at 1 and 3 months post-injection (MPI). PFF-injected mice developed proteinase K-resistant phosphorylated α-syn pathology in hippocampal subfields and entorhinal cortex. Absence in α-syn-knockout mice at 5MPI supported dependence on endogenous α-syn. Pathology was accompanied by neuronal degeneration and increased glial immunoreactivity, particularly in the dentate gyrus, alongside increased CCR2 + area consistent with monocyte recruitment. Cognitive impairments varied by task and time point, with greater anxiety-like behavior at 3 MPI. Peripheral immune profiles varied primarily by sex and time. These findings characterize neuroimmune changes and selective nonmotor behavioral abnormalities, supporting this hippocampal PFF model as a valuable tool for investigating LBD mechanisms.