Elucidating the Role of Altered Axonal Lysosome Transport in Alzheimer’s Disease
Principal Investigator
Project Goals
A robust feature of Alzheimer’s disease (AD) brain pathology is the accumulation of lysosomes (digestive organelles of cells) in swollen neuronal axons that surround amyloid plaques. How these lysosomes come to accumulate and what their role is in AD has not been established. While a major function of lysosomes is to degrade proteins, our recent work investigating these plaque-associated lysosomes demonstrated that they lack the enzymes required for efficient protein degradation. This suggests a model wherein amyloid plaques cause a blockade in the transport and maturation of lysosomes in surrounding neuronal axons. These immature lysosomes appear to contain the machinery required to make more of the amyloid beta (Aß) peptide that is the major component of amyloid plaques. Thus, the interactions between amyloid plaques and neuronal axons are predicted to result in a vicious cycle that contributes to further disease pathology. My proposed research aims to test this hypothesis comprehensively by establishing a neuronal primary culture model for such axonal lysosome transport defects. This system will be amenable to drug manipulations and genetic disruption to elucidate both the mechanisms that control lysosome biogenesis and transport in neuronal axons, as well as the impact of impaired lysosome transport on the amyloidogenic processing of the amyloid precursor protein (APP). I will furthermore investigate the effects of lysosome axonal transport defects on AD brain pathology (such as amyloid plaque growth and number) through the use of genetic disruption in a mouse model of AD.
Project Summary
Amyloid plaques are a defining feature of the Alzheimer’s disease (AD) brain. These plaques have an impact on surrounding neurons in that axons that contact the plaques appear swollen and are filled with lysosomes. The mechanisms whereby plaques trigger such changes in neuronal axons, and their contributions, to the disease process remains unknown. While a major function of lysosomes is to degrade proteins, we have previously found that the lysosomes that accumulate at amyloid plaques are strikingly deficient in their degradative enzyme content. We suspect that amyloid plaques cause a blockade in the transport and maturation of lysosomes in surrounding neuronal axons. While these plaque-associated lysosomes are deficient in their normal degradative functions, they appear to contain the machinery required to make the amyloid beta (Aß) peptide that is the major component of amyloid plaques. We hypothesize that this relationship between amyloid plaques, lysosomes within surrounding neuronal axons and Aß synthesis results in a vicious circle that contributes to further disease pathology.
Our ongoing research is testing this hypothesis by establishing a neuronal primary culture model for systematically investigating the relationship between axonal lysosome transport and maturation. It will serve as a model of the defects that arise in the AD brain (Specific Aim 1). This simplified neuronal cell culture system gives us precise temporal control over the process and allows us to directly examine cause-effect relationships.
We are also testing the relationship between axonal lysosome transport and Aß metabolism (Specific Aim 2). For example, we are assessing whether axonal lysosome accumulation is sufficient to cause increased Aß production.
Lastly, we are investigating the effects of lysosome axonal transport defects on AD brain pathology (such as amyloid plaque growth and number) through the use of genetic perturbations in a mouse model of AD (Specific Aim 3).
Collectively, these efforts are expected to provide understanding of the mechanisms whereby amyloid plaques trigger the accumulation of lysosomes in surrounding axons, as well as the contribution of such lysosomes to the disease process. Such insights will help to determine whether restoration of normal axonal transport and maturation of lysosome should be pursued as a therapeutic strategy.
First published on: July 20, 2016
Last modified on: November 23, 2024