A 4R tauopathy develops without amyloid deposits in aged cat brains

Abstract

Human tauopathies are neurodegenerative diseases with accumulation of abnormally phosphorylated and aggregated tau proteins forming neurofibrillary tangles. We investigated the development of tau pathology in aged cat brains as a model of neurofibrillary tangle formation occurring spontaneously during aging. In 4 of 6 cats aged between 18 and 21 years, we found a somatodendritic accumulation of phosphorylated and aggregated tau in neurons and oligodendrocytes. Two of these 4 cats had no amyloid immunoreactivity. These tau inclusions were mainly composed of 4R tau isoforms and straight filaments and colocalized with the active form of the glycogen synthase kinase-3 (GSK3). Cat brains with a tau pathology showed a significant cortical atrophy and neuronal loss. We demonstrate in this study the presence of a tau pathology in aged cat brains that develop independently of amyloid deposits. The colocalization of the active form of the GSK3 with tau inclusions as observed in human tauopathies suggests that this kinase could be responsible for the abnormal tau phosphorylation observed in aged cat brains, representing a mechanism of tau pathology development shared between a naturally occurring tauopathy in aged cats and human tauopathies.

Aging pet cats develop neuropathology similar to human Alzheimer’s disease

“…Alternative splicing of MAPT yields a total of 6 isoforms in the human adult brain. Specifically, the isoforms differ by the number of amino acids inserted at the N terminal aspect of the protein (0, 1 or 2 producing 0N, 1N or 2N) and by the presence of three or four amino acid repeats (3R and 4R) in the C terminal part of the protein, which contain the microtubule binding domains [13]. In AD (a taupathy), tau is shifted from primarily axonal locations to a somatic-dendritic distribution, becomes hyperphosphorylated, ubiquinated, and loses its ability to bind to microtubules, resulting in a misfolded, insoluble tau protein.…”

“…In addition, the active form glycogen synthase kinase-3 (GSK3), a tau protein kinase, has been found in association with tau lesions and at increased expression levels in AD brains [13]. Tau aggregates may be present in the neuron cell body, dendrites, and axons.…”

“…Ultrastructurally, tau aggregates in AD are made of two filaments paired in a helical structure (PHFs). Straight filaments have also been seen, but usually these are more suggestive of other taupathies such as progressive supranuclear palsy (PSP) and Pick's disease (PiD) [13]. In general, the development of Aβ plaques is considered to precede and accentuate the develop of NFTs in human AD [14].…”

“…Aging cats have been shown to develop tauopathies that share many features to human AD. For example, adult cats express 6 total tau isoforms, including the hyperphosphorylated 3R and 4R isoforms, which can form aggregates in the presence of Aβ as in human AD [6,13].…”

“…These features of feline NFTs accompanied by neuronal loss and occurring in intracellular oligomers in the same brain region (hippocampus), have also been described in transgenic mouse models and human AD patients, and thus represent a potentially high impact naturally occurring model of the disease [5] compared to pet dogs and NHP's ( Figure 2). Although most other aging nonhuman animals do not spontaneously develop NFTs and neuronal loss, abnormal tau phosphorylation has been described in a number of species including sheep and goats, bison, bears, degu, and wolverines [1,13]. Dogs have not been shown to develop NFTs, but do show increased phorphorylation of tau that may represent pretangle pathology.…”