Sep. 27, 2023
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Microtubule-associated protein-tau (MAPT) has been linked to more neurodegenerative diseases than any other protein. Collectively known as tauopathies, these disorders arise from the accumulation of abnormally folded MAPT in the brain (14; 17). These groups of diseases are heterogeneous in nature due to inclusions involving different areas of the brain, different cell types, or different tau isoforms (15). Some diseases classically associated with MAPT pathology include Alzheimer disease, frontotemporal dementia with parkinsonism, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. In addition, there is growing evidence that MAPT may be involved in other prominent neurodegenerative diseases, such as Parkinson disease, Huntington disease, and treatment-refractory epilepsy. It remains to be revealed to what extent MAPT plays a primary versus secondary role in the mechanisms behind these diverse conditions. This article covers discoveries in the understanding of the pathology and pathophysiology of MAPT.
• Microtubule-associated protein-tau (MAPT) or tau is a protein that stabilizes microtubules to facilitate axonal transport and maintain neuronal integrity.
• Tauopathies are diverse neurodegenerative diseases characterized by inclusions of abnormal tau deposited in different areas or cells of the brain leading to heterogeneous clinical features.
• Pathologically, abnormal MAPT causes disease when insoluble filaments aggregate in neurons and astroglial cells and propagate between cells in neural networks in a prion-like fashion.
• Biomarkers and disease-modifying therapies aimed at tauopathies target the pathogenesis of MAPT at various stages, including hyperphosphorylation of tau, filament aggregation, and microtubule stabilization.
Alzheimer disease was the first disorder to be identified as a tauopathy when Alois Alzheimer described a dementing illness characterized on pathology by neuritic plaques and intracellular neurofibrillary tangles in the cerebral cortex (17). Electron microscopy performed by Michael Kidd in 1963 then identified paired helical filament as the prominent structural component in neurofibrillary tangles. Hyperphosphorylated MAPT was ultimately recognized in the 1990s as the major component of paired helical filament and straight filament in brains with Alzheimer disease. Additionally, all six isoforms of MAPT were identified in the neurofibrillary tangles associated with Alzheimer disease. In 1996, genetic linkage analysis identified an autosomal dominant disorder in 13 families with frontotemporal dementia and parkinsonism (08). These disorders were labeled FTDP-17 to recognize the clinical features of this genetic disorder and the identification of the mutation on chromosome 17. Soon after identification of this disorder, the term “tauopathy” was used and widely accepted as a name for any disorder in which the prominent feature is tau protein deposition (13). In 1998, the first mutation in the MAPT gene was identified in association with FTDP-17 (08). Since then, over 50 mutations in the MAPT gene have been found in hereditary neurodegenerative diseases that demonstrate pathologic aggregates of abnormal tau protein (17).
The pathologic identification of MAPT inclusions in postmortem brains has broadened our understanding of neurodegenerative diseases and changed our clinical terminology over the years. This is best understood through the history of Alzheimer disease definition. As pathologists identified MAPT in neurofibrillary tangles and beta-amyloid plaques as the features of Alzheimer disease, the definition of the disorder began to link the clinical findings of progressive cognitive impairment with the pathology seen in postmortem brains. This led to the terms “probable Alzheimer disease” and “definitive Alzheimer disease,” first noted in 1984, one defined as clinical cognitive impairment with impaired daily functioning and the other the same clinical picture with proven plaques and tangles on postmortem autopsy respectively (12). The term mild cognitive impairment became utilized in the 1990s as clinicians began to identify patients with cognitive impairment without impaired daily functioning, a disorder considered to be a prodrome to Alzheimer disease. Longitudinal studies, however, have shown that mild cognitive impairment is not specific to Alzheimer disease; pathologic studies have shown a variety of mixed pathologic findings that included plaques and tangles but also abnormalities such as alpha-synuclein inclusions, hippocampal sclerosis, and other tauopathies. The reverse has also been shown to be true: patients with nonamnestic cognitive disorders could also have pathologic plaques and tangles. These included corticobasal syndrome, logopenic primary progressive aphasia, and dysexecutive syndrome to name a few. The definition of dementia, specifically Alzheimer dementia, once again broadened to now include impairment in two cognitive domains without a requirement for memory impairment.
Pathologically, probable Alzheimer disease is now understood to be a heterogeneous group of disorders. In 1997, neuropathologists adopted a definition of Alzheimer disease based solely on the presence, amount, and location of plaques and tangles on postmortem analysis. This shift now identified a number of patients who were cognitively intact around the time of death but who pathologically had Alzheimer disease. Since this time, there has been a push for separating the clinical disorder from the disease found in the brain, highlighting the need for biomarkers that identify the pathologic process occurring in brain tissue regardless of the clinical picture. This has been further supported by National Institute on Aging- Alzheimer’s Association diagnostic criteria for Alzheimer disease (11). Additionally, tau has been identified in older adults in neurofibrillary tangles that are indistinguishable from those seen in Alzheimer disease. Yet these patients lack amyloid plaques and are clinically heterogeneous, ranging from cognitively intact to dementia. This group of disorders is now known as “primary age-related tauopathy” (PART), and a consensus guideline on the neuropathologic identification of these disorders once again pushes for a decoupling of pathologic classification from clinical diagnosis (05).
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