Niemann Pick type C disease as a model to study the amyloid hypothesis of neurodegeneration. Michael Castello* ( 3/2011 - 9/2014 )
Although Alzheimer’s disease (AD) has been actively researched for several decades, little is known about the pathogenesis of the disease. The prevailing “amyloid cascade hypothesis” suggests that the generation and accumulation of the amyloid peptide Aβ, a cleavage product of the Amyloid Precursor Protein (APP), precedes, and leads to, abnormal phosphorylation of tau, which aggregates to form neurofibrilary tangles that disable neurons, ultimately leading to cell death and dementia. A reasonable approach to study the function of Aβ a neurodegenerative trigger would involve the use of an AD model without the ability to generate Aβ from APP. Unfortunately, without knowledge of how or why Aβ protein first begins to accumulate, current cellular and animal models focus on generating Aβ and studying the downstream effects - rendering them of little use when attempting to determine the initial cause of the Aβ accumulation. Interestingly, Niemann-Pick disease type C (NPC) patients, in whom cholesterol and other lipids accumulate in late endosomes and lysosomes, also demonstrate accumulation of Aβ and phosphorylated tau, and ultimate neurodegeneration - seemingly invoking the amyloid hypothesis. Unlike AD, the primary cause of NPC is straightforward: the gene for one of the NPC proteins is mutated. If the amyloid cascade hypothesis can indeed be translated to NPC, it would suggest that a key part of NPC pathogenesis might be the generation of Aβ, eventually contributing to the neuronal dysfunction and death that characterize NPC. In our lab, we are testing this notion directly in mouse models of NPC by removing the ability of the animals to generate Aβ.