Many of the most devastating and scientifically vexing neurodegenerative diseases seen in the VA clinic today are linked by the abnormal neuronal accumulation of the microtubule-stabilizing protein, tau (MAPT). Tau inclusions are hallmarks of diseases that include Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), frontotemporal dementia / parkinsonism linked to chromosome 17 (FTDP-17T), and a particular form of amyotrophic lateral sclerosis (ALS) connected to mutations in TDP-43. These conditions (collectively known as ?tauopathies?) are marked by accumulation of hyper-phosphorylated, filamentous aggregates of tau protein, which, however, occur in different brain regions and with somewhat variable structures. The purpose of this study is to determine whether the primary cilium, a tiny microtubule-based organelle that projects from the surface of nearly every cell type, including neurons, glia, and cells of the vascular tree within the brain, constitutes a previously unrecognized locus of injury in tauopathies. As proof of concept, our study will focus specifically on how cilia become altered in mouse models of Alzheimer's disease. As AD progresses, tau fails to perform its normal role to stabilize microtubules. In the classical view, this leads to axonal destabilization and loss of neuronal connectivity. However, we hypothesize that an additional casualty of this microtubule destabilization is the primary cilium, which requires several types of microtubules to grow and maintain its structural integrity. This leads to interference with cilia-localized signaling pathways (e.g. sonic hedgehog, p75NTR, and Wnt), resulting in loss of adult neuronal homeostasis. Here we seek pilot funding to develop animal models that will allow us to evaluate how changes in ciliary structure are correlated with pathological markers of the disease (Specific Aim #1). This aspect of the project will take advantage of our experience in imaging the tiny primary cilium using unbiased imaging approaches developed in our lab.
In Specific Aim #2 we will generate an inducible animal model that will allow us to eliminate primary cilia in the cortex and hippocampus of AD mice. This will enable us to quantify how ablation of cilia at specified time points affects neurodegenerative progression. Until now the primary cilium has been largely overlooked as a possible target in tauopathies. These results may provide the first steps towards a unifying explanation for some of the more common features of tau-based neurodegenerative disorders. !
Surveys show that in the U.S. the prospect of developing Alzheimer's disease is now more feared than getting cancer. Alzheimer's disease and other types of dementias, widespread in the aging VA population, are frequently referred to as ?tauopathies? because they have in common a defective protein known as tau. Faulty tau causes architectural elements of the cell known as microtubules to collapse. An inconspicuous, but very important cellular feature known as the primary cilium is present on all cells of the brain, and it also needs microtubules to maintain its functional and structural integrity. Loss of the primary cilium is linked to many diseases known as ?ciliopathies?. This project seeks to understand the connection between !tauopathies like Alzheimer's disease and ciliopathies, and may therefore reveal a completely new site of injury in neurodegeneration.
