| MAPT — Microtubule-Associated Protein Tau | |
|---|---|
| Symbol | MAPT |
| Full Name | Microtubule-Associated Protein Tau |
| Chromosome | 17q21.31 |
| NCBI Gene | 4137 |
| Ensembl | ENSG00000193962 |
| OMIM | 157140 |
| UniProt | P10636 |
| Diseases | Alzheimer's Disease, PSP, CBD, FTD |
| Expression | [Neurons](/entities/neurons) (neurons), Axons, [Hippocampus](/brain-regions/hippocampus), [Cortex](/brain-regions/cortex) |
| Key Haplotypes & Mutations | |
| H1/H2 haplotypes; P301L, P301S, R406W (FTDP-17) | |
MAPT (Microtubule-Associated Protein Tau) is a gene located on chromosome 17q21.31 that encodes the tau protein — the central pathological player in Alzheimer's disease and related tauopathies. The discovery that tau forms the paired helical filaments and neurofibrillary tangles (NFTs) characteristic of AD revolutionized our understanding of neurodegeneration[1]. MAPT is essential for axonal transport and neuronal viability, and mutations or dysregulation of MAPT lead to a spectrum of diseases collectively termed tauopathies.
The MAPT gene is notable for its complex genomic architecture, including a ~900 kb inversion that creates two distinct haplotypes (H1 and H2) in European populations. The H1 haplotype is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease[2][3].
The MAPT gene spans approximately 150 kb on chromosome 17q21.31. The H1 and H2 haplotypes arose from a single inversion event and are in strong linkage disequilibrium with specific variants. The H1 haplotype is the ancestral and more common form (~75% in Europeans) and is associated with increased risk for multiple tauopathies. The H2 haplotype appears to be protective against PSP[2:1].
The MAPT gene consists of 16 exons with complex alternative splicing. The central region (exons 2, 3, and 10) undergoes tissue-specific and developmentally regulated splicing, generating six major isoforms in the adult human brain[4][5]:
| Isoform | N-terminal Inserts | Microtubule-Binding Repeats | Length |
|---|---|---|---|
| 0N3R | None | 3 repeats | 352 aa |
| 0N4R | None | 4 repeats | 383 aa |
| 1N3R | One insert | 3 repeats | 379 aa |
| 1N4R | One insert | 4 repeats | 410 aa |
| 2N3R | Two inserts | 3 repeats | 395 aa |
| 2N4R | Two inserts | 4 repeats | 441 aa |
The balance between 3R and 4R tau isoforms is critical — imbalances contribute to pathology in several tauopathies. Exon 10 encoding the second microtubule-binding repeat is particularly relevant to disease pathogenesis.
MAPT expression is modulated by multiple mechanisms:
The tau protein is produced in six isoforms (352-441 amino acids) with three functional domains[7]:
N-terminal Projection Domain (residues 1-250): Projects away from microtubule surface, mediating interactions with neuronal membranes and kinases.
Proline-Rich Region (residues 151-243): Contains 85+ phosphorylation sites, mediates interactions with src-family kinases.
Microtubule-Binding Domain (residues 244-368): Contains 3-4 tandem repeat sequences (R1-R4) that bind to microtubules.
C-terminal Region (residues 369-441): Acidic tail regulating protein-protein interactions.
Tau exists in multiple states[7:1]:
The primary function of tau is to bind and stabilize microtubules, essential for axonal transport and neuronal polarity[8]. Tau promotes microtubule polymerization by reducing the critical concentration of tubulin required for assembly and increasing the rate of microtubule nucleation. The N-terminal domain maintains proper spacing between microtubules in axons.
By stabilizing microtubules, tau indirectly supports axonal transport via motor proteins kinesin and dynein. Hyperphosphorylation reduces tau-microtubule binding, releasing tau and impairing axonal transport — a well-documented early event in neurodegeneration[9].
Tau localizes to synapses where it may regulate synaptic plasticity, mitochondrial trafficking, and neuronal signaling. Tau can be secreted in an activity-dependent manner, potentially serving as a propagation vector in tauopathies[10].
High expression in:
Expression data from Allen Human Brain Atlas.
In AD, tau becomes abnormally hyperphosphorylated, aggregating into paired helical filaments (PHFs) and straight filaments that form neurofibrillary tangles[11]. NFT density correlates strongly with cognitive decline. Progression follows a predictable pattern: entorhinal cortex → hippocampus → limbic system → isocortex.
Key phosphorylation sites in AD[12]:
Over 50 pathogenic mutations in MAPT cause FTDP-17, inherited in autosomal dominant fashion. Mutations either alter exon 10 splicing (P301L, P301S, N279K) or reduce microtubule binding (K257T, G272V)[13].
Strongly associated with the H1 haplotype of MAPT, particularly the H1c sub-haplotype. Characterized by 4R tau accumulation in globose NFTs and tufted astrocytes, affecting the basal ganglia, brainstem, and cerebellar nuclei[14].
Another 4R tauopathy associated with MAPT H1 haplotype. Pathological tau forms astrocytic plaques and corticobasal balloons. Shares and distinct genetic risk factors with PSP[15].
NFT pathology primarily in the medial temporal lobe without significant amyloid plaques. The relationship between MAPT haplotypes and PART is still being characterized[16].
| Mutation | Effect | Disease |
|---|---|---|
| P301L | ↓ microtubule binding, ↑ aggregation | FTDP-17, CBD |
| P301S | ↓ microtubule binding, ↑ aggregation | FTDP-17 |
| K257T | ↓ microtubule binding | FTDP-17 |
| R406W | ↑ aggregation, altered binding | FTDP-17 |
| N279K | Alters splicing → 4R | FTDP-17 |
| S305S | Alters splicing → 4R | FTDP-17 |
Tau pathology spreads through connected neural networks in a prion-like manner[23][24]:
Soluble tau oligomers are highly toxic — they disrupt synaptic function, impair mitochondrial function, activate inflammation, and serve as seeds for further aggregation.
| Interactor | Role | Effect on Pathology |
|---|---|---|
| GSK3-beta | Kinase | Major tau kinase, hyperphosphorylates multiple sites |
| PP2A | Phosphatase | Accounts for ~70% of tau phosphatase activity |
| CDK5 | Kinase | Neuron-specific, phosphorylates Ser202/Thr205 |
| Fyn kinase | Tyrosine kinase | Mediates tau neurotoxicity |
| Pin1 | Prolyl isomerase | Regulates tau conformation |
| Hsp90 | Chaperone | Stabilizes mutant tau |
Over 85 phosphorylation sites on tau. Balance between kinases (GSK3beta, CDK5, MARK, DYRK1A) and phosphatases (PP2A ~70% of activity) determines phosphorylation state. PP2A activity is reduced ~50% in AD brains.
Reduced in AD brains, can compete with phosphorylation — may protect against aggregation.
At K280, K369 promotes aggregation and reduces microtubule binding. SIRT1 deacetylase can remove these modifications.
Ballard C, et al. Alzheimer's disease. Lancet. 2011. ↩︎
Connor C, et al. The MAPT H1 haplotype is a risk factor for progressive supranuclear palsy. Neurology. 2009. ↩︎ ↩︎
Allen M, et al. Association of MAPT haplotypes with Alzheimer's disease risk and neuropathology. Neurobiol Aging. 2012. ↩︎
Andreadis A. Tau gene alternative splicing: pathological mechanisms in the regulation of tau protein. J Mol Neurosci. 2006. ↩︎
Goedert M, et al. Tau isoforms: differential expression in Alzheimer's disease and other tauopathies. Brain Pathol. 2006. ↩︎
He L, et al. MicroRNA regulation of MAPT expression. Acta Neuropathol Commun. 2015. ↩︎
Mandelkow E, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2010. ↩︎ ↩︎
Baas PW, et al. Tau promotes microtubule severing. J Cell Sci. 2013. ↩︎
Stamer K, et al. Tau blocks traffic of organelles from the cell body to the neurite. J Neurosci. 2002. ↩︎
Pooler AM, et al. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013. ↩︎
Braak H, et al. Staging of Alzheimer disease-related neurofibrillary changes. Neurobiol Aging. 1995. ↩︎
Gong CX, et al. Regulation of tau phosphorylation by PP2A. Acta Neurobiol Exp (Wars). 2004. ↩︎ ↩︎
Hutton M, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998. ↩︎
Williams DR, et al. Progressive supranuclear palsy: clinicopathological concepts. Lancet Neurol. 2007. ↩︎
Ghetti B, et al. Corticobasal degeneration: a distinctive pattern of tau pathology. Acta Neuropathol. 2015. ↩︎
Crary JF, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014. ↩︎
Delenclos M, et al. Tau-based therapeutic approaches for Alzheimer's disease. Nat Rev Neurol. 2019. ↩︎
Boutajangout A, et al. Tau immunotherapy. J Alzheimers Dis. 2010. ↩︎
Wischik CM, et al. Tau aggregation inhibitors. J Alzheimers Dis. 2015. ↩︎
DeVos SL, et al. Antisense oligonucleotides for tau. Neuron. 2017. ↩︎
Schindler SE, et al. Plasma p-tau217 accurately detects Alzheimer's disease. Nat Med. 2020. ↩︎
Scholl M, et al. PET imaging of tau pathology in Alzheimer's disease. Nat Rev Neurol. 2017. ↩︎
Guo JL, Lee VM. Seeding of tau aggregation. Nat Med. 2011. ↩︎
Frost B, et al. Tau propagation in vivo. J Neurosci. 2009. ↩︎
Min SW, et al. Acetylation of tau in neurodegeneration. Nat Med. 2010. ↩︎