Alzheimer’s disease (AD) begins silently, often decades before symptoms appear. A key early step in AD is the buildup of toxic amyloid beta, which forms plaques and damages brain cells. Amyloid beta is produced inside small compartments in neurons called endosomes, and the protein RAB5 regulates its production. Recent studies show that when RAB5 becomes overactive, endosomes become abnormally enlarged. This change is seen very early in AD, even before amyloid plaque buildup or memory loss begins.
Dr. Bhattacharyya’s earlier CureAlz-funded work identified two AD risk genes, RIN3 and BIN1, that affect amyloid beta production by influencing RAB5 activity. RIN3 activates RAB5 and promotes the production of amyloid beta. RIN3 can also recruit BIN1 to the endosome and bind to it. BIN1 binding inhibits RIN3’s ability to activate RAB5, preventing endosomes from becoming abnormally enlarged and slowing amyloid beta production. Mutations in RIN3 associated with AD prevent this binding, leading to uncontrolled RAB5 activity and enlarged endosomes. While we know that these enlarged endosomes are seen very early in AD, we do not know whether endosomal dysfunction drives the disease. Dr. Bhattacharyya’s lab hypothesizes that it does. Establishing this link would justify targeting early endosomal dysfunction therapeutically to combat AD.
To test this hypothesis, the Bhattacharyya lab will pursue two experimental aims. In the first, they will examine the connection between early-stage endosomal pathology and amyloid or tau pathology in cell culture experiments. They will compare neurons with normal RIN3 and BIN1 genes, mutated versions of the genes, and those with the genes knocked out. Since the mutated genes are risk factors for late-onset AD, they will also compare these results with neurons carrying familial AD mutations to determine whether there are shared characteristics and pathologies between late-onset and familial AD. This will involve closely monitoring various aspects of the amyloid processing machinery and the levels of several tau forms in these models. Building on these cellular findings, the second aim will then focus on how this system operates in mice. The Bhattacharyya lab intends to cross a RIN3 knockout mouse model with an amyloid mouse model to examine how the loss of RIN3 affects amyloid pathology and cognitive decline. They believe that the lack of RIN3 will limit the extent of endosomal enlargement, which, in turn, will limit amyloid pathology and cognitive deficits in these mice.
This project offers the potential to open new avenues for earlier therapeutic intervention against AD. Limiting endosomal dysfunction in neurons could preserve synaptic function while staving off amyloid and tau pathology. This study represents a key step toward such a potential approach.
