Early Amyloid Formation and Neuroinflammatory Response in a Bigenic Mouse Model Expressing Human α-Synuclein and Aβ

Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and dementia with Lewy bodies. A common feature of these disorders is the misfolding and aggregation of α-synuclein (α-syn) and amyloid-β (Aβ) proteins into amyloid structures, which disrupt cellular homoeostasis and drive disease progression. While Aβ typically forms extracellular deposits and α-syn accumulates in intracellular inclusions, both ultimately contribute to neuronal damage and neurodegeneration. Increasing in vitro evidence suggests that these proteins can interact, altering their structural properties and, in turn, their biological effects; however, the consequences of their co-occurrence in vivo remain unclear. To address this gap, we examined whether α-syn modulates Aβ deposition and associated neuroinflammation at early stages using a physiologically relevant bigenic mouse model coexpressing human α-syn and APP knock-in Aβ. Using combined histological and biochemical analysis, we characterised Aβ load and microglial responses at early time points. Our results indicate that α-syn expression is associated with altered early Aβ deposition and microglial morphology in vivo. Specifically, while early Aβ deposits were detected in both Aβ/α-syn and Aβ-control mice from 2 months of age, at 4 and 6 months, reduced number and size of Aβ microdeposits was observed in the Aβ/α-syn model. The reduction in Aβ load was accompanied by a more ramified microglial morphology consistent with a less activated microglial state. Whether this delayed response reflects protection or impaired immune surveillance remains unclear. Our findings highlight the complexity of indirect Aβ and α-syn interactions and the need for further studies to clarify their functional impact. The newly generated bigenic mice provide a relevant platform to investigate early co-pathology and its role in disease progression.