The Effectiveness of UBE3A to Reduce Tau Pathology
College
College of Arts and Sciences
Mentor Information
Kevin Nash
Description
Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by the buildup of amyloid plaques, neurofibrillary tangles (NFTs) and cognitive impairment. NFTs are caused by the buildup and aggregation of the Tau protein due to hyperphosphorylation. Damaged proteins are degraded through the ubiquitin-proteasome system, however, this system is dysregulated in AD leading to protein accumulation. UBE3A, one of many proteins that are responsible for ubiquitination of proteins for degradation, is reduced in AD. Therefore, we hypothesized that overexpression of UBE3A in mouse models with tau overexpression may lead to improved pathological outcomes. We used the Tg4510 mouse model which has a P301L mutation of human tau. Recombinant Adeno-associated virus serotype 9 (rAAV9) was utilized to express a secreted version of UBE3A (rAAV9-STUB, n=8) or control green fluorescent protein (GFP, n=9) in 3 mo old Tg4510 mice. Virus was administered through bilateral intracranial injections into the hippocampus and anterior cortex. Non-transgenic mice (n=10) were used as controls. After carrying out behavior tests, the mice were euthanized and their brains were analyzed via immunohistochemistry experiment (IHC) to investigate hyperphosphorylation at serine 396 residue of the tau protein. Experiments are underway to study neurodegeneration using levels of neuronal nuclei and NFTs through Gallyas staining. Pathological changes are being investigated in areas responsible for cognitive functioning (hippocampus and cortex). Since AAV9-STUB mice had better behavior outcomes than AAV9-GFP control mice, we hypothesize a decrease in NFTs and an increase in neuronal density—indicating the effectiveness of UBE3A to decrease tau pathology in mice.
The Effectiveness of UBE3A to Reduce Tau Pathology
Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by the buildup of amyloid plaques, neurofibrillary tangles (NFTs) and cognitive impairment. NFTs are caused by the buildup and aggregation of the Tau protein due to hyperphosphorylation. Damaged proteins are degraded through the ubiquitin-proteasome system, however, this system is dysregulated in AD leading to protein accumulation. UBE3A, one of many proteins that are responsible for ubiquitination of proteins for degradation, is reduced in AD. Therefore, we hypothesized that overexpression of UBE3A in mouse models with tau overexpression may lead to improved pathological outcomes. We used the Tg4510 mouse model which has a P301L mutation of human tau. Recombinant Adeno-associated virus serotype 9 (rAAV9) was utilized to express a secreted version of UBE3A (rAAV9-STUB, n=8) or control green fluorescent protein (GFP, n=9) in 3 mo old Tg4510 mice. Virus was administered through bilateral intracranial injections into the hippocampus and anterior cortex. Non-transgenic mice (n=10) were used as controls. After carrying out behavior tests, the mice were euthanized and their brains were analyzed via immunohistochemistry experiment (IHC) to investigate hyperphosphorylation at serine 396 residue of the tau protein. Experiments are underway to study neurodegeneration using levels of neuronal nuclei and NFTs through Gallyas staining. Pathological changes are being investigated in areas responsible for cognitive functioning (hippocampus and cortex). Since AAV9-STUB mice had better behavior outcomes than AAV9-GFP control mice, we hypothesize a decrease in NFTs and an increase in neuronal density—indicating the effectiveness of UBE3A to decrease tau pathology in mice.
