Author: Emmanuel Prikas
Prikas, Emmanuel, 2023 The role of tau and tau-associated protein networks in memory circuits and processes, Flinders University, College of Medicine and Public Health
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Neuroplasticity is a fundamental permissive feature of our brain that allows for processes of learning and memory. Our ability to think, adapt, and flourish in our environment across the lifespan depends on the dynamic connectivity and communication between neurons, known as synaptic plasticity.
The first chapter of this thesis begins with a comprehensive overview of our evolving conceptualisations of learning and memory. Ancient western philosophical notions on the nature of thoughts-in-mind as either pre-existing (idealism) or gathered from interaction with the environment (empiricism), provided the epistemological framework for how we understand contemporary neuroscientific research. To this end, we gather information using quantifiable behaviourist approaches and remain aware of ethological notions of inherited species-specific characteristics to understand and interpret our results. In describing memory research, I arrive at the ‘engram’: a latent but enduring physical-chemical change in the brain that was provoked through learning; a neural correlate or representation of a memory. Categorical and formal definitions of memory are then linked to their molecular mechanistic underpinnings in long-term potentiation and depression. These molecular memory mechanisms can impair as we age, and independently become dysfunctional in neurodegenerative disorders such as Alzheimer’s Disease (AD). Alzheimer’s Disease is characterised by brain tissue lesions from depositions of the aggregated microtubule-associated protein tau. Impaired memory is an early clinical symptom of AD and has been linked to synaptic dysfunction and pathologic redistribution of axonal tau to synapses and the cell soma. The tau protein is a central factor in AD and other tauopathies. I hypothesised that by identifying tau protein-protein interactions (PPIs) in physiologic conditions, we can gain a better understanding of the role of tau in neurodegenerative diseases.
This hypothesis was addressed in chapter 2, presenting published research on our proximity labelling proteomics approach to charting functional tau interactomes in primary neurons and mouse brain. I fused a modified biotin ligase, BioID2, to the N-terminus of full-length human tau protein (BioID2-tau), which biotinylated stable and transient tau interactors when expressed in biotin-enriched brain tissue. Tau interactors mapped onto pathways of cytoskeletal, post-synaptic receptor, and synaptic vesicle regulation and showed enrichment for Alzheimer’s and Parkinson’s diseases. Tau interacts with and inhibits the activity of vesicular ATPase N-ethylmaleimide sensitive fusion protein (NSF), which is essential for trafficking of glutamate receptor (AMPAR). Tau-deficient (tau-/-) neurons showed aberrant localization of NSF and synaptic AMPAR surface levels, reversible through tau expression or NSF inhibition. Consequently, enhanced associative and object recognition memory, mediated by AMPAR, is suppressed in tau-/- mice by both hippocampal tau and infusion with an NSF-inhibiting peptide. Pathologic tau from AD mouse models and human AD samples enhances inhibition of NSF. Our results map neuronal tau interactomes and delineate a physiologic and pathologic functional link of tau with NSF that regulates plasticity associated AMPAR shuttling and memory performance.
Tau-associated interactions in neurons may be mediating memory (engram) cell function within neural networks. Whether there are tau interactions that mediate specific engram function of a cell ensemble supporting learning/memory of a specific task is unknown. My aim in chapter 3 was to identify tau and tau-associated protein-protein interactions (PPIs) in engrams by harnessing the necessarily activity-dependent functions in memory engram cells. To address this, I fused an enhanced biotin ligase, MiniTurboID, to tau, under the expressional control of a modified neuronal activity-dependent promoter. I mapped the interactome of tau by labelling proteins in two spatial memory-associated engrams in hippocampus of tau-/- mice during a spatial memory paradigm. Among these were five central tau interactors, Sh3gl2, CamK2a, MeCP2, Ppp3ca, and Lin7c that occur in specific engram states when compared to general tau interactomes, in memory non-specific neurons. This suggests that these PPIs underlie memory processes and may be defined by engram-specific tau interactions at temporally significant points across persistent engram function, including learning, consolidation, maintenance, and retrieval from latency.
Keywords: BioID, TurboID, protein interaction, tau, dementia, Alzheimer's Disease, memory, engram, learning, biotinylation
Subject: Neuroscience thesis
Thesis type: Doctor of Philosophy
Completed: 2023
School: College of Medicine and Public Health
Supervisor: Arne Ittner