Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Tau protein stabilizes microtubules, crucial for neuronal function.
• Abnormal tau accumulation is linked to neurodegenerative diseases, including Alzheimer disease (AD), Chronic Traumatic Encephalopathy (CTE), and Traumatic Brain Injury (TBI).
• Post-translational modifications (PTMs) of tau, such as phosphorylation, lead to its toxic gain of function.

Purpose of the Study:

• To investigate the mechanisms by which pathological human tau (PH-Tau) induces cognitive decline.
• To characterize the cellular and molecular consequences of PH-Tau expression in a transgenic mouse model.
• To explore the role of tau in proteostasis during neurodegeneration.

Main Methods:

• Generation of a transgenic mouse model expressing varying concentrations of PH-Tau in neurons.
• Assessment of cognitive function in PH-Tau expressing mice.
• Microscopic analysis of neuronal morphology, axonal integrity, and synaptic terminals.
• Investigation of tau's subcellular localization and potential involvement in proteostasis.

Main Results:

• PH-Tau expression leads to cognitive decline through at least two distinct pathways.
• High PH-Tau concentrations cause axonal disruption via cytoskeleton involvement.
• Lower PH-Tau concentrations alter synaptic terminals with minimal apparent neuronal morphology changes.
• PH-Tau induces subcellular mislocalization, including nuclear translocation.

Conclusions:

• Pathological tau contributes to neurodegeneration via multiple mechanisms affecting neuronal structure and function.
• Understanding tau's behavior on and off microtubules is key to elucidating neurodegenerative processes.
• Tau's role in proteostasis warrants further investigation in the context of neurodegenerative diseases.