Feline Dementia May Explain Synapse Loss in Alzheimers

By Pooja Toshniwal PahariaReviewed by Lauren HardakerAug 20 2025

In a study published in the European Journal of Neuroscience, researchers explored amyloid-beta (Aβ)-driven neuroinflammation and synapse loss in feline cognitive dysfunction syndrome (CDS). They also evaluated the value of feline CDS as a translational model for Alzheimer’s disease (AD). They found Aβ accumulation within synapses and increased glial-mediated synaptic engulfment in aged and CDS-affected feline brains, mirroring synaptic pathology in human AD.

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The findings enhance our understanding of AD pathogenesis and suggest that glial-mediated synapse loss may represent a therapeutic target for cognitive decline.

Feline CDS refers to age-associated neurodegeneration, like human dementia, marked by behavioral abnormalities like increased nocturnal vocalization, altered social interaction, disorientation, anxiety, sleep-wake disturbances, and impaired memory. The exact mechanisms behind feline CDS remain unclear; however, key neuropathological features observed in AD (including cerebral atrophy, neuronal death, Aβ deposition, tauopathy, and congophilic angiopathy) also occur in cats undergoing aging and cognitive decline.

Emerging evidence suggests that neuroinflammation and synaptic loss, characteristics of AD, might also contribute to feline CDS; however, these processes remain largely unexplored. In particular, the role of synaptic Aβ accumulation and glial-mediated synaptic engulfment in the feline CDS is unclear. Whether Aβ-associated pathology follows a regionally progressive pattern in cats, as in AD, and contributes to synaptic loss remains an open question.

About The Study

In the present study, researchers determined whether Aβ contributes directly to neuroinflammation and synaptic loss in the feline brain rather than being a benign age-related finding. They assessed whether Aβ accumulates in synapses and promotes glial-mediated synaptic engulfment in feline CDS, thereby deciphering mechanisms relevant to human AD.

To investigate the mechanisms underlying synaptic loss in feline CDS, the researchers analyzed post-mortem brain tissue from cats diagnosed with CDS based on VISHDAAL criteria. These animals exhibited behavioral changes for at least three months that are non-attributable to any other medical condition.

The team examined the parietal lobe of seven young, 10 aged, and eight CDS-affected cat samples using immunohistochemistry (IHC) and confocal microscopy. To assess synaptic Aβ accumulation and glial-mediated synaptic engulfment, they immunostained brain sections for Aβ, synaptic markers, astrocytes, and microglia. The researchers used four different molecular markers to identify specific brain structures and cell types: 4G8 to label amyloid-beta deposits, synapsin-1 to highlight synapses, glial fibrillary acidic protein (GFAP) to mark astrocytes, and ionized calcium binding adaptor molecule 1 (IBA1) to detect microglia.

The researchers compared brain samples from age-matched cats with and without CDS (mean age, 17 years) with those of young cats (mean age, five years) without neurological disease. The comparisons revealed neuropathological changes associated with CDS and aging. Linear mixed-effects modeling (LMEM) enabled statistical analysis.

Results

The results revealed striking parallels between feline CDS and human AD, providing novel insights into Aβ-associated synaptic degeneration. Consistent with findings in human AD, Aβ accumulated directly within synapses of brain cortices obtained from aged cats and those with CDS. The team found that synaptic Aβ accumulation was strongly associated with increased activation of microglial cells and astrocytes, reflecting marked neuroinflammation.

In samples representative of aging and cognitive dysfunction, the researchers observed microgliosis and astrogliosis in regions displaying Aβ plaques, resulting in prominent synaptic engulfment by glial cells. Importantly, triple colocalization analyses revealed that microglia and astrocytes internalized Aβ-containing synapses, suggesting that Aβ induces aberrant synaptic pruning by glia in the feline brain.

Although aged and CDS-affected cats had comparable overall Aβ loads, only the CDS group demonstrated Aβ burden in correlation with the extent of synaptic engulfment by glia. The findings suggest that dysregulated glial responses, particularly in the background of cognitive impairment, drive synaptic loss. In contrast, aged cats without CDS did not show this correlation, suggesting that Aβ-associated glial activity had a greater local impact in CDS than in normal aging.

Conclusions

The study findings demonstrate that amyloid beta proteins are associated with pathogenic effects on feline brains and may drive synaptic loss through glial-mediated degeneration, closely resembling processes observed in human cases of AD. The study, therefore, provides supporting evidence that feline CDS is a natural and clinically relevant model of AD for studying AD-related synaptic degeneration. Scientists can leverage the feline CDS model to investigate Aβ-driven synaptic changes and evaluate therapeutic strategies to understand or potentially alter glial-mediated synapse loss.

Future studies could include larger cohorts and higher-resolution techniques such as light and electron microscopy to characterize synaptic Aβ accumulation and clarify whether glial cells target degenerating or functional synapses in feline CDS. The molecular mechanisms underlying Aβ-induced synaptotoxicity also require further investigation.

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Journal Reference

McGeachan, R. I., et al. (2025). Amyloid-Beta Pathology Increases Synaptic Engulfment by Glia in Feline Cognitive Dysfunction Syndrome: A Naturally Occurring Model of Alzheimer's Disease. European Journal of Neuroscience, 62(3), e70180, DOI: 10.1111/ejn.70180. https://onlinelibrary.wiley.com/doi/10.1111/ejn.70180