Exploring the Link between pTau Accumulation and CASM Deficiency in Cognitive Decline
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Mentor Information
Dr. Bradlee Heckmann
Description
The human brain has 86 billion neurons, which form 100 trillion connections with each other. These connections are supported by microtubules, which make up the axons and dendrites of neurons. Tau proteins stabilize microtubules by connecting microtubule fragments together preventing disintegration. In pathological conditions, tau proteins experiencing post-translational phosphorylation become hyperphosphorylated (pTau) resulting in reduced binding affinity to the microtubule, breaking down neurons. Excess pTau oligomerizes to form neurofibrillary tangles leading to neurodegeneration. Clearance systems like conjugation of ATG8s to single membranes (CASM) and pathways within CASM like LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO) regulate pTau accumulation. The purpose of this project is to explore whether a deficiency in CASM leads to cognitive deficits in humanized mouse models with tau pathology. This is investigated by using WT & Rubicon-Knockout hTau mouse models mutated to overexpress humanized tau via exogenous microtubule-associated protein tau (MAPT) gene expression. After 6-9 months, the mice groups undergo behavioral and electrophysiological analysis to test cognition, anxiety levels, and strength of hippocampus action potentials. Immunostaining and Western Blot is used to identify/quantify pTau and Iba1 accumulation (Iba1, a marker for microglia activation/inflammation). Anticipated results show Rubicon-Knockout hTau mice reveal increased pTau and Iba1 accumulation, impaired memory, increased anxiety, and decreased action potential within the hippocampus all of which suggest cognitive decline and neuroinflammation. We plan to further dissect the role of CASM in pTau regulation, explore the downstream effects of tau pathology, and discover novel solutions to inhibit the impacts of pathological tau through drug discovery.
Exploring the Link between pTau Accumulation and CASM Deficiency in Cognitive Decline
The human brain has 86 billion neurons, which form 100 trillion connections with each other. These connections are supported by microtubules, which make up the axons and dendrites of neurons. Tau proteins stabilize microtubules by connecting microtubule fragments together preventing disintegration. In pathological conditions, tau proteins experiencing post-translational phosphorylation become hyperphosphorylated (pTau) resulting in reduced binding affinity to the microtubule, breaking down neurons. Excess pTau oligomerizes to form neurofibrillary tangles leading to neurodegeneration. Clearance systems like conjugation of ATG8s to single membranes (CASM) and pathways within CASM like LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO) regulate pTau accumulation. The purpose of this project is to explore whether a deficiency in CASM leads to cognitive deficits in humanized mouse models with tau pathology. This is investigated by using WT & Rubicon-Knockout hTau mouse models mutated to overexpress humanized tau via exogenous microtubule-associated protein tau (MAPT) gene expression. After 6-9 months, the mice groups undergo behavioral and electrophysiological analysis to test cognition, anxiety levels, and strength of hippocampus action potentials. Immunostaining and Western Blot is used to identify/quantify pTau and Iba1 accumulation (Iba1, a marker for microglia activation/inflammation). Anticipated results show Rubicon-Knockout hTau mice reveal increased pTau and Iba1 accumulation, impaired memory, increased anxiety, and decreased action potential within the hippocampus all of which suggest cognitive decline and neuroinflammation. We plan to further dissect the role of CASM in pTau regulation, explore the downstream effects of tau pathology, and discover novel solutions to inhibit the impacts of pathological tau through drug discovery.
