Elucidating the Basis for Memory Impairment in Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease that shares clinical features with Alzheimer’s disease (dementia) and Parkinson’s disease (movement disorder). Diagnosis is confirmed at autopsy by the presence of Lewy bodies in the brain. These intracellular protein aggregates containing α-synuclein are thought to impair movement when in the brainstem, yet it remains unclear whether they impair memory when in the hippocampus. Genetics have also been implicated in DLB in that certain mutations increase the risk of developing the disease. However, the links between these genetic alterations and neuronal dysfunction are not fully established.To address these issues, we pursued two complementary approaches: 1) we characterized hippocampal Lewy pathology burden and distribution in 95 autopsy-confirmed DLB cases, correlating these pathology data to results from memory testing; 2) we reprogrammed fibroblasts from clinically diagnosed DLB patients and relevant controls into neurons with a direct conversion method, then used them to investigate differential gene expression and resulting functional differences.Lewy pathology in our postmortem DLB cases was predominant in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing memory dysfunction. Lewy pathology in CA1—the main output region for CA2—correlated best with results from memory testing despite a milder pathology, suggesting that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. To probe the mechanisms leading to neuronal dysfunction in a dynamic system, we reprogrammed DLB patient fibroblasts to induced neurons (iNs). These iNs displayed multiple neuronal features, including the expression of specific markers. We conducted RNA-sequencing to compare patient and control lines, and found genes relating to synaptic function (including the gene for α-synuclein) and oxidative stress upregulated in the iNs, as opposed to the parent fibroblast lines which had very few differentially expressed genes. We confirmed the increase in α-synuclein at the protein level via staining, and mapped the “DLB signature” we identified to a pro-inflammatory state, offering potential new avenues for screening and intervention in the disease