A Novel Approach to the Study of Mechanisms in Alzheimer’s Disease

Overview

Alzheimer’s disease (AD) currently remains the sixth leading cause of death in the US. Despite decades of research devoted to understanding AD, a cure does not exist. Many researchers have focused their attention on abnormal plaques and tangles characteristic of AD. However, these approaches have not proven fruitful. Instead, exploring alternative hypotheses, including the faulty neuronal cell cycle and astrogliosis, could be integral to understanding Alzheimer’s disease pathology. Primary cilia, which are non-motile sensory organelles found in most brain cells, regulate signaling pathways involved in cell cycle function and astrogliosis. Researching this organelle could advance current understandings of aberrant cellular mechanisms in AD. This study analyzed changes in primary cilia morphology as indicators of aberrant cilia. The hypotheses were that: (1) aberrant cilia could be allowing post-mitotic neurons to abnormally undergo mitosis, thus causing widespread neuronal death in Alzheimer’s, and (2) dysfunction in astrocyte primary cilia could contribute to faulty cellular signaling, resulting in Alzheimer’s-related astrogliosis. Immunohistochemistry was used to stain for cilia in postmortem human Alzheimer’s disease tissue and age-matched control tissue. This study is the first to observe and characterize cilia in human disease tissue. Different cell types were stained to determine the types of cells associated with cilia in the human brain. This project is the first to observe the presence of astrocyte cilia in the human brain. Changes in cilia morphology were quantified. The numerical density of cilia increased in Alzheimer’s tissue compared to age-matched control tissue. The cilia were identified as astrocyte cilia. Numerical density of astrocytes increased by two-fold in Alzheimer’s tissue. Half of all Alzheimer’s cilia observed were fragmented, an abnormality that has not been previously observed. Cilia fragmentation may disrupt the cilia-dependent sonic hedgehog signaling pathways, causing exacerbation of astrogliosis in AD. Fragmentation could also be preventing cilia from inhibiting re-entry of astrocytes into the cell cycle, causing a rapid proliferation of astrocytes as observed in Alzheimer’s disease. Some astrocytes appeared to have more than one cilia. This phenomenon suggests that multiple centrosomes may exist within one cell, which could cause abnormal cell cycle processes. Primary cilia in Alzheimer’s disease present significant changes in morphology. Multiple cilia in astrocytes and cilia fragmentation suggest that aberrant cilia in astrocytes could result in faulty cellular signaling, leading to astrogliosis in Alzheimer’s. Additional research is necessary to determine particular signaling pathways affected by aberrant cilia function in Alzheimer’s. Future analysis of cilia morphology and function in Alzheimer’s disease could aid in identifying potential drug targets for disease treatment.

Competition history

• AJAS 2018 Category not listed

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