Wojtas, Aleksandra

Abstract Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by α-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, AD is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analysed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNA sequencing from the anterior cingulate cortex and determined differentially expressed genes (q-value <0.05) in control (n = 81), LBD (n = 436), AD (n = 53) and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis to understand the pathways associated with each neuropathologically defined group. LBD cases had strong upregulation of inflammatory pathways and downregulation of metabolic pathways. The LBD cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the LBD cohorts consistently showed upregulation for genes involved in protein folding and cytokine immune response, as well as downregulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the LBD cases resulted in no additional changes. Some core inflammatory pathways were shared between AD and LBD but with numerous disease-specific changes. Direct comparison of LBD cohorts versus AD cases revealed strong enrichment of synaptic signalling, behaviour and neuronal system pathways. Females had a stronger response overall in both LBD and AD, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined LBD and AD cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.

AbstractBackgroundLewy body dementia (LBD) is one of the most common causes of dementia and is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of alpha‐synuclein in the form of Lewy bodies and neurites. Many of these individuals also have concomitant neuropathological changes such as vascular disease, tangles, and TDP‐43. Like in Alzheimer’s disease, APOE4 is the most significant genetic risk factor for the development of LBD. We sought to survey the landscape of transcriptional changes in the cingulate cortex from a large cohort of LBD cases (>400) compared to normal controls of both sexes.MethodWe performed bulk tissue RNAseq and aligned reads to a human reference genome that is informed on the sex chromosome complement of the sample. Differentially expressed genes were determined after genome‐wide correction.ResultWe found a core set of transcriptional changes that were shared between both sexes in pathways related to neuronal functions and inflammation. However, we also identified numerous changes in genetic female samples that were not significantly altered in genetic males, or that were significantly altered but in the opposite direction. Similar male‐specific changes were also found. These alterations were present for genes on both sex chromosomes as well as autosomes. Though cohort sizes were smaller, we also compared this dataset to Alzheimer’s disease and found shared but unique transcriptional alterations.ConclusionOverall, genetic males and females exhibit sex‐shared and sex‐specific gene expression patterns in dementia with Lewy bodies. We are currently assessing splice alterations, running causal gene network analysis, and performing histological validation.

Significance Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.