Amyloid-Beta Pathology Increases Synaptic Engulfment by Glia in Feline Cognitive Dysfunction Syndrome: A Naturally Occurring Model of Alzheimer's Disease.

Feline cognitive dysfunction syndrome (CDS; a.k.a. feline dementia) is an age-related neurodegenerative disorder, comparable to dementia in people, characterised by behavioural changes such as increased vocalisation, altered social interactions, sleep-wake cycle, disorientation and house-soiling. Although the underlying mechanisms remain poorly understood, pathologies similar to those observed in Alzheimer's disease (AD) have been identified in the brains of aged or CDS-affected cats, including brain atrophy, neuronal loss, amyloid-beta plaques, tau pathology and cerebral amyloid angiopathy. Neuroinflammation and synapse loss, other important hallmarks of AD, may also play important roles in feline ageing and CDS, but these are yet to be explored. Several mechanisms of synapse loss have been described in human AD and mouse models of amyloidopathy, including synaptic accumulation of amyloid-beta and the aberrant induction of synaptic engulfment by microglia and astrocytes. In this study, immunohistochemistry and confocal microscopy were used to examine the parietal cortex of young (n = 7), aged (n = 10) and CDS-affected (n = 8) cats. Linear mixed effect modelling revealed that amyloid-beta accumulates within synapses in the aged and CDS-affected brain. Additionally, in the aged and CDS groups, there was microgliosis, astrogliosis and increased synaptic engulfment by microglia and astrocytes in regions with Aβ plaques. Further, microglia and astrocytes show increased internalisation of amyloid-beta-containing synapses near plaques. These findings suggest that amyloid-beta exerts a pathogenic effect in the feline brain, with mechanisms mirroring those seen in human AD. Importantly, these results support the use of feline CDS as a naturally occurring, translational model of Alzheimer's disease, offering valuable insights into AD pathogenesis and potential therapeutic targets.