Region-specific tau phosphorylation and microtubule pathology following α-synuclein exposure in the mouse brain: biochemical and ultrastructural evidence.
TL;DR
Findings indicate that ASN oligomers induce selective, region-specific dysregulation of tau phosphorylation that co-occurs with neuronal MT disorganisation and cytoskeletal abnormalities in the mouse brain.
Abstract
Accumulating evidence indicates that pathological interactions between -synuclein (ASN) and tau contribute to the progression of -synucleinopathies; however, the mechanisms linking ASN exposure to tau dysregulation and neuronal cytoskeletal pathology remain incompletely understood. In the present study, we investigated whether bilateral intrastriatal injection of ASN oligomers induces alterations in tau phosphorylation associated with microtubule (MT) abnormalities in the mouse brain. Western blot analyses were performed in the striatum, midbrain, and cortex at 180 days post-injection to assess tau phosphorylation at disease-associated epitopes (Ser199/202, Ser404, and Ser416) together with / -tubulin levels. Ultrastructural changes in neuronal cytoskeletal organisation were evaluated qualitatively using transmission electron microscopy (TEM). ASN exposure induced selective, bidirectional, site- and region-specific changes in tau phosphorylation rather than uniform hyperphosphorylation. Increased p-tau(Ser199/202) levels were observed in the striatum and cortex, whereas p-tau(Ser404) was elevated in the midbrain but decreased in the cortex. No significant changes in p-tau(Ser416) or / -tubulin levels were detected in any analysed brain region. TEM analyses further revealed disrupted neuronal MT organisation, characterised by fragmented and loosely packed MT networks, reduced MT abundance, and occasional loss of cytoskeletal elements accompanied by axonal or synaptic swelling, despite preserved total / -tubulin levels. Collectively, our findings indicate that ASN oligomers induce selective, region-specific dysregulation of tau phosphorylation that co-occurs with neuronal MT disorganisation and cytoskeletal abnormalities. Together, these findings support a link between ASN-induced, site- and region-specific tau dysregulation and neuronal cytoskeletal pathology in -synucleinopathies.