Parkinson’s disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak’s theory and model where pathological α‐synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson’s disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α‐synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson’s disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.
Alzheimer's disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of Alzheimer's disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer's disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer's disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer's disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer's disease, illuminating GWAS identification of sex-specific Alzheimer's risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer's disease.
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