The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Abstract

Introduction: Alternative splicing of the human MAPT gene generates six brain-specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations.

Methods: A comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server.

Results: While TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive.

Discussion: In this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU-associated diseases.

Highlights: MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development-, cell-type and brain region specific. The contribution of TAU to neurodegeneration might be isoform-specific. Ineffective TAU-based therapies highlight the need for specific targeting strategies.

Keywords: Alzheimer's disease; MAPT; TAU isoforms; alternative splicing; genetic tauopathy; tauopathy.

FIGURE 1

Alternative splicing of the human MAPT gene. The human MAPT gene encodes for six brain‐specific TAU isoforms based on alternative splicing of exons 2, 3, and 10. The TAU protein can be structured into four different domains: The N‐terminal projection domain, which projects away from the microtubules (MTs), acts as a spacer and interacts with components of the plasma membrane. The proline‐rich region is involved in cellular signalling by interacting with Src‐familiy kinases such as Fyn. The MT‐binding domain mediates MT polymerization and stability, and the C‐terminal region additionally contributes to MT polymerization and TAU's interaction with the plasma membrane. Figure created with BioRender.com

FIGURE 2

TAU functions in health and disease. In healthy neurons, TAU is enriched in the axon, where it binds and enables MTs to form long labile/ dynamic domains. A small fraction of TAU is reported to be localized in in the soma, dendrites and the nucleus. Interactome and functional studies highlight the diverse roles of TAU in various cellular contexts. For example, by interacting with DNA and RNA, TAU can influence transcription and translation. Dendritic TAU enhances dendrite and spine maturation and may be important for synaptic activity. During neuronal development, TAU facilitates axonal outgrowth and growth cone dynamics and later has a role in synapse formation and synaptic transmission. Under pathological conditions, such as extracellular aggregation of amyloid beta plaques, TAU dissociates from axonal MTs, accumulates in in the somatodendritic compartment, and gets hyperphosphorylated. Due to the phosphorylation, TAU changes its conformation, which increases its aggregation propensity and results in the accumulation of TAU assemblies in NFTs. Reduction of the MT‐bound TAU results in changes of MT dynamics and leads to impairments of downstream functions, such as axonal transport, which ultimately drives synaptic dysfunction and neuronal cell death. Furthermore, TAU missorting into the dendrites causes postsynaptic spine loss and NMDA receptor mediated excitotoxicity driving cognitive decline. Furthermore, somatic or missorted TAU can inhibit translation, and cause proteasomal and mitochondrial dysfunction. At the pre‐synapse TAU further contributes to synaptic dysfunction and can spread trans‐synaptically to receiving neurons, possibly mediating the progression of the pathology. Figure created with BioRender.com