Tau pathology in canine dementia exhibits cellular and regional distribution that reflects early stage human Alzheimer’s disease
Regenerative Neuroscience Group, Brain and Mind Centre, University of Sydney, New South Wales, Australia
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with pathological hallmarks including amyloid-β plaques, tau tangles, and neuronal loss. These pathologies follow a highly stereotyped distribution and progression pattern and contribute to brain dysfunction. To date, have been no available disease modifying therapies, partially due to overreliance on transgenic rodent preclinical models that do not sufficiently recapitulate complex AD pathology. There is thus a need for preclinical models with more translational and predictive validity.
Over 14% of canines naturally present with canine cognitive dysfunction (CCD), an age-related human dementia-like syndrome. CCD dogs have quantifiable orientation and memory deficits, which, alongside their similar neuroanatomy and shared domestic environment, may make them ideal models. However, while Aβ plaque pathology has been demonstrated in CCD dogs, open questions remain regarding tau pathology.
To characterise tauopathy, we examined 6 CCD and 6 non-CCD dogs using enhanced immunohistochemical methods across an array of brain regions to attempt pathological staging and evaluate the hypothesis that CCD reflects early stage human AD (hAD) neuropathology. We assessed phospho-S396 tau, an early marker of tauopathy quantified by automated image analysis, and AT8+ neurofibrillary pathology.
We found AT8+ neurons in only one dog near the transentorhinal cortex, but significantly greater S396+ immunoreactivity in all CCD dogs, specific to regions such as the thalamus and temporal lobe, implicated in early hAD. Double immunofluorescence showed S396+ NFT-like aggregations in neuronal axons and somata. Overall, tauopathy in CCD particularly affected structures of the Papez Circuit, essential to episodic memory and affected in hAD.
This preliminary evidence shows a regionally specific pattern of early-stage tau pathology in CCD dogs that roughly conforms to early stage hAD. Additional research is required to understand the diverse nature of CCD neuropathology and further validate it as a preclinical model of human AD.