Increased interactions and engulfment of dendrites by microglia precede Purkinje cell degeneration in a mouse model of Niemann Pick Type-C.

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia in the molecular layer (ML) are activated and contacting dendrites at early stages of NPC, when no loss of PCs is detected. During the progression of PCs degeneration in Npc1nmf164 mice, accumulation of phagosomes and autofluorescent material in microglia at the ML coincided with the degeneration of dendrites and PCs. Feeding Npc1nmf164 mice a western diet (WD) increased microglia activation and corresponded with a more extensive degeneration of dendrites but not PC somata. Together our data suggest that microglia contribute to the degeneration of PCs by interacting, engulfing and phagocytosing their dendrites while the cell somata are still present

Investigating the effects of APOE-£4 on angiogenesis and blood brain barrier integrity in early stages of cerebrovascular development

Although there are many forms of dementia, vascular dementia is gaining attention because of the contributions that vascular health can have on the development of dementia. In this study, analysis of transverse and coronal images of the developing mouse brain has confirmed the best method for visualizing embryonic brain vasculature. Throughout this study, we use immunohistochemistry to understand the physiological phenomena occurring as early as the embryonic stages and how tl1e Apoe gene may be affecting development. The goals of this study are to understand the mechanism of angiogenesis and look for the presence of astrocytes and microglia~ two types of cells suspected of expressing Apoe. These findings will allow us to speculate how eacl1 may play a role in the development of the embryonic brain vasculature. This study further opens tlp potential for investigating how, if present, human Apoe genotype (hApoe) expression from microglia and astrocytes at emb:ryonic day 15 (El5) could lead to early signs of development of Alzheimer\u27s Disease or dementia. In the future, we will compare the amount of microglia and astrocytes present across three genotypes (hApoee3h 3, hApoee3te4, and hApoee4te4) to detect noticeable differences in development of vasculature in the brain of embryonic mice to possibly support the hypothesis that Apoem, the greatest genetic rislc factor for late onset Alzheimer\u27s Disease1, affects vascular development long before typical phenotypes of AD and dementia are detected