Microglia signatures in the hippocampus of Alzheimer's Disease and Dementia with Lewy bodies patients

Worldwide more than 55 million people are suffering from incurable age-related neurodegenerative diseases and associated dementia, including Alzheimer’s Disease (AD) and Dementia with Lewy bodies (DLB). AD and DLB patients share memory impairment symptoms but present specific deterioration patterns of the hippocampus, a brain region essential for memory processes. Notably, the CA1 subregion is more vulnerable to atrophy in AD patients than in DLB patients. However, it remains unclear which factors contribute to this differential subregional vulnerability. On the neuropathological level, both AD and DLB patients frequently present an overlap of misfolded protein pathologies with AD-typical pathologies including extracellular amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein (pTau), and DLB-typical pathological inclusions of phosphorylated 𝛼-synuclein (pSyn). Recent genome-wide association studies (GWAS) have revealed many genetic AD risk factors that are directly linked to microglia and suggest that they play an active role in pathology. However, how microglia alterations are linked to local pathological environments and which role microglia subpopulations play in specific vulnerability patterns of the hippocampus in AD and DLB remains poorly understood. This PhD thesis addressed two main aspects of microglia alterations in the post-mortem hippocampus of AD and DLB patients. The first study provided a very detailed and 3D characterization of microglia alterations at individual cell levels across CA1, CA3 and DG/CA4 subfields; and their local association with concomitant pTau, Aβ and pSyn loads across AD and DLB. We show that the co-occurrence of these three different types of misfolded proteins is frequent and follows specific subregional patterns in both diseases but is more severe in AD than DLB cases. Our results suggest that high burdens of pTau and pSyn associated with increased microglial alterations could be associated to the CA1 vulnerability in AD. Our second study provided an morphological and molecular characterization of a type of microglia accumulations referred to as coffin-like microglia (CoM), using high- and super-resolution microscopy as well as digital spatial profiling. We showed that CoM were enriched in the pyramidal layer of CA1/CA2 and were not linked to Aβ plaques, but occasionally engulfed or contained NFTs or intraneuronal granular pSyn inclusions. Furthermore, CoM are not surrounded by hypertrophic reactive astrocytes like plaque-associated microglia (PAM), but rather by dystrophic astrocytic processes. We found that proteomic and transcriptomic signatures of CoM point toward cellular senescence and immune cell infiltration, while PAM signatures indicate oxido-reductase activity and lipid degradation. Our studies provide new insights in complex signatures of human microglia in the hippocampus of age-related neurodegenerative diseases.