Combinatory effect of proteinopathies on microglia responses in mixed-dementia hippocampus
The hippocampus deterioration is at the centre of memory decline in the most common age- and dementia-related neurodegenerative diseases: Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB). However, its subregional atrophy pattern differs between both diseases, the CA1 subfield being more severely affected in AD patients. AD and DLB cases often share mixed proteinopathies patterns that complexify our understanding of the neurodegenerative processes at play. We hypothesized that the distribution and severity of the main AD and DLB proteinopathies, as well as the alteration of microglia, the brain innate immune cells, could dictate the local vulnerability of the hippocampus in AD. We measured volumetric loads of each proteinopathy, quantified and classified 3D morphologies of individual microglia, in three subfields on a collection of fixed hippocampus samples of a collection of neuropathologically assessed late-onset AD (n=11) and DLB (n=7) cases, sharing frequently mixed proteinopathies, and age-matched control subjects (n=11).
Across AD and DLB samples, we found that the subregional load patterns were specific to the type of proteinopathy, whereas the degree of their severity was related to the condition, AD samples showing heavier burdens. We found P-Tau and P-Syn accumulations particularly exacerbated in CA1 AD. We report strong positive correlations between P-Tau and P-Syn loads across subfields and conditions. In a second part, we assessed the changes in the subregional microglia signatures by measuring 16 morphological features of more than 35,000 individual microglia and classifying them into seven morphological clusters. Some feature variations were associated with conditions and/or subfields. We found some morphological features selectively impacted by one or a pair of proteinopathies. We found strong associations subfield-dependent between disease morphological clusters and P-Tau, Aß and P-Syn loads.