Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat.

Dystrophic axons and terminals are common in the myenteric plexus and smooth muscle of the gastrointestinal (GI) tract of aged rats. In young adult rats, alpha-synuclein in its normal state is abundant throughout the myenteric plexus, making this protein-which is prone to fibrillization-a candidate marker for axonopathies in the aged rat. To determine if aggregation of alpha-synuclein is involved in the formation of age-related enteric neuropathies, we sampled the stomach, small intestine and large intestine of adult, middle-aged, and aged virgin male Fischer 344 rats stained for alpha-synuclein in both its normal and pathological states. Alpha-synuclein-positive dystrophic axons and terminals were present throughout the GI tract of middle-aged and aged rats, with immunohistochemical double labeling demonstrating co-localization within nitric oxide synthase-, calretinin-, calbindin-, or tyrosine hydroxylase-positive markedly swollen neurites. However, other dystrophic neurites positive for each of these four markers were not co-reactive for alpha-synuclein. Similarly, a subpopulation of alpha-synuclein inclusions contained deposits immunostained with an anti-tau phospho-specific Ser(262) antibody, but not all of these hyperphosphorylated tau-positive aggregates were co-localized with alpha-synuclein. The presence of heteroplastic and potentially degenerating neural elements and protein aggregates both positive and negative for alpha-synuclein suggests a complex chronological relationship between the onset of degenerative changes and the accumulation of misfolded proteins. Additionally, proteins other than alpha-synuclein appear to be involved in age-related axonopathies. Finally, this study establishes the utility of the aging Fischer 344 rat for the study of synucleopathies and tauopathies in the GI tract.