Characterization of microtubule-associated protein tau isoforms and Alzheimer's disease-like pathology in normal sheep (Ovis aries): relevance to their potential as a model of Alzheimer's disease

Alzheimer's disease is a chronic neurodegenerative disease that accounts for up to 80% of all demential. Characterised by deteriorations of memory and cognitive function, the key neuropathological features are accumulations of beta-amyloid and hyperphosphorylated tau, as 'plaques' and 'tangles', respectively. Despite extensive study, however, the exact mechanism underlying aggregate formation in Alzheimer's disease remains elusive, as does the contribution of these aggregates to disease progression. Importantly, a recent evaluation of current Alzheimer's disease animal models suggested that rodent models are not able to fully recapitulate the pathological intricacies of the disease as it occurs in humans. Therefore, increasing attention is being paid to species that might make good alternatives to rodents for studying the molecular pathology of Alzheimer's disease. The sheep (Ovis aries) is one such species, although to date, there have been few molecular studies relating to Alzheimer's disease in sheep. Here, we investigated the Alzheimer's disease relevant histopathological characteristics of 22 sheep, using anti-p-amyloid (Abeam 12267 and mOC64) and phosphorylation specific anti-tau (AT8 and S396) antibodies. We identified numerous intraneuronal aggregates of both beta-amyloid and tau that are consistent with early Alzheimer's disease-like pathology. We confirmed the expression of two 3-repeat (1N3R, 2N3R) and two 4-repeat (1N4R, 2N4R) tau isoforms in the ovine brain, which result from the alternative splicing of two tau exons. Finally, we investigated the phosphorylation status of the serine396 residue in 30 sheep, and report that the phosphorylation of this residue begins in sheep aged as young as 2 years. Together, these data show that sheep exhibit naturally occurring beta-amyloid and tau pathologies, that reflect those that occur in the early stages of Alzheimer's disease. This is an important step towards the validation of the sheep as a feasible large animal species in which to model Alzheimer's disease.

Automated summary

Alzheimer's disease is a chronic neurodegenerative disease, and the exact mechanism and pathological characteristics are still unclear. Recent studies have suggested that rodent models are not adequate for studying the disease, leading to increased attention on alternative animal models, such as sheep. This study found that sheep naturally exhibit beta-amyloid and tau pathologies similar to early stages of Alzheimer's disease, which highlights the importance of using sheep as a feasible large animal model for studying the disease.