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

Abstract

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 Ser262 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.

The bowel and beyond: the enteric nervous system in neurological disorders

“…Aβ-immunoreactive plaques were reported in the intestinal submucosa of two patients with AD 118 , but there have been no follow-up studies. Human enteric neurons express microtubule-associated tau protein 119,120 and hyperphosphorylated tau aggregates have also been detected in the myenteric plexus of ageing rats 121 . Only one study has compared the ENS in patients with AD with that of healthy individuals and those with other forms of dementia, in which no enteric neuronal loss or tau pathology specific to AD was found 122 .…”

Aging of the mammalian gastrointestinal tract: a complex organ system

“…Protein aggregation is another possible mechanism of cellular aging in the gut; α-synuclein aggregates have been demonstrated in aging gut neurons (Phillips et al 2009). …”

The Aging Colon: The Role of Enteric Neurodegeneration in Constipation

“…In rodent models of PD induced by prototypical parkinsonian neurotoxin MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), rotenone, or unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neurons, the loss of enteric dopaminergic neurons is associated with abnormal colonic contractility leading to a marked inhibition of propulsive motility and daily fecal pellet output [21,[25][26][27]. Although the loss of dopaminergic neurons in the ENS may be a contributing factor to constipation in PD, the presynaptic protein α-synuclein has also been implicated in changes in the ENS in the aging gut [28,29]. Specifically, studies in rodent models have shown that α-synuclein is expressed in a subpopulation of myenteric neurons and in vagal terminals.…”

“…Specifically, studies in rodent models have shown that α-synuclein is expressed in a subpopulation of myenteric neurons and in vagal terminals. The α-synuclein is coexpressed with nitric oxide synthase (NOS) or with markers of cholinergic neurons, and α-synuclein immunopositive aggregates have been observed within the myenteric plexus of aging rats [28,29]. Additionally, evidence exists of abnormal colonic motility in mice overexpressing human wild-type α-synuclein [30].…”