Tauopathies are a class of

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

s characterized by the aggregation of abnormal

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

Hyperphosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

of tau proteins causes them to dissociate from

microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...

s and form insoluble aggregates called

neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...

s. Various neuropathologic

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

s have been described based on the anatomical regions and cell types involved as well as the unique tau

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

making up these deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies'. Some neuropathologic phenotypes involving tau protein are

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

frontotemporal dementia Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal lobe, frontal and tempor ...

progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

, and

corticobasal degeneration Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and typical survival before death is eight years. It is cha ...

Tau protein

Tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

, also called tubulin associated unit or microtubule-associated protein tau (MAPT), is a

-associated protein that promotes polymerization and stabilization into microtubules by binding to tubulin. Variants of Tau

, spanning from 352 to 441 amino acids, arise through the alternative splicing of exons 2, 3 and 10 within the MAPT gene. The six isoforms are differentiated by the inclusion and exclusion of inserts of either 29 or 58 amino acids in the N-terminus domain. Furthermore, the isoforms are categorized based on the presence of either three (3R tau isoforms) or four (4R tau isoforms) tandem repeat sequences each consisting of 31 or 32 amino acids.

Biomarkers

Neuroimaging

Positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

(PET) is one type of

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

capable of identifying elevated levels of tau in patients with Alzheimer's disease. PET is a great tool that can supplement information such as regions with higher neuropathologic burden than others. But it needs to be eligible, and have more positive outcomes than negative, such as exposure to radioactivity.

Biofluid

The analysis of

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

(CSF) represents a potential avenue for the development of biomarkers in tauopathies. Substantial data on CSF biomarkers is available for Alzheimer's disease (AD), focusing on measures related to total and phosphorylated forms of tau and amyloid-beta (Aβ) protein. Elevated CSF tau and decreased Aβ levels constitute the characteristic CSF signature of AD, allowing differentiation from controls. This signature may also assist in distinguishing atypical forms of AD pathology associated with clinical frontotemporal dementia (FTD) from those with underlying frontotemporal lobar degeneration (FTLD)-Tau pathology.

Alzheimer's disease

(AD) is clinically characterized by a progressive decline in memory and cognitive functions, leading to severe dementia. Microscopically, AD is identified by the presence of two types of insoluble fibrous materials: (1) extracellular amyloid (Aβ) protein forming senile plaques and (2) intracellular neurofibrillary lesions (NFL) composed of abnormally and hyperphosphorylated tau protein. While AD is not strictly considered a prototypical tauopathy, as tau pathology coexists with Aβ protein deposition, the 'amyloid cascade hypothesis' posits that Aβ accumulation is the primary factor driving AD pathogenesis. Nevertheless, AD neurofibrillary lesions were the first to undergo ultrastructural and biochemical analysis, thus laying the foundation for in-depth studies on tau protein deposition in various tauopathies.

Neuropathologic phenotypes

Frontotemporal dementia

Frontotemporal dementia Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal lobe, frontal and tempor ...

is a part of a diverse spectrum of disorders clinically marked by dysfunction in the frontal and temporal lobes, collectively referred to as

frontotemporal lobar degeneration Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes. Com ...

(FTLD). The primary histological characteristics include profound neuronal loss, enlarged neurons, and distinctive spherical argyrophilic inclusions known as Pick bodies (PBs). These PBs primarily consist of hyperphosphorylated tau protein, with tau protein presenting as two major bands at 60 and 64 kDa and a variable, minor band at 69 kDa. Filamentous tau deposits in nerve cells are predominantly composed of 3R tau isoforms.

Progressive supranuclear palsy

Progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

(PSP) is a type of tauopathy, but the cause is not yet discovered. For PSP unusual phosphorylation for tau protein causes vital protein filaments in the nerve cells to destruct, a phenomenon called "neurofibrillary" degeneration. Typical symptoms of PSP would be abnormal speech, balance impairment and overcognitive and memory impairment. As CBD, PSP is also classified as a 4R tauopathy, and because of that PSP will often be selected for trials regarding anti-tau therapeutics.

Corticobasal degeneration

Corticobasal degeneration Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and typical survival before death is eight years. It is cha ...

(CBD) is an increasingly acknowledged neurodegenerative disorder characterized by both motor and cognitive dysfunction. In affected regions, histological examination reveals pronounced neuronal loss accompanied by spongiosis and gliosis, cortical ballooned cells, and notable intracytoplasmic filamentous tau pathology in both glial and neuronal cells. Biochemically, the distinctive tau profile in CBD cases manifests as a prominent tau doublet at 64 and 68 kDa, which is variably identified. These bands predominantly consist of hyperphosphorylated 4R tau isoforms, leading to the classification of CBD as a 4R tauopathy.

Tau therapeutics

Currently, there are no specific treatments for tauopathies. Up till now, attempts have been made to target neurotransmitter disturbances to relieve disease symptoms. For AD a specific treatment is difficult because the pathological changes both early compared to the symptoms showing. Even though there is no current treatment for tauopathies, there are treatments that can relieve symptoms. Speech therapy can be beneficial for aphasia symptoms, symptoms such as depression and apathy are frequently engaged with pharmaceuticals. For physical challenges, physical therapy has proven helpful in extending motor function for patients.

Other diseases

Primary age-related tauopathy Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur ...

(PART) dementia, with NFTs similar to AD, but without

amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...

. *

Chronic traumatic encephalopathy Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets wor ...

(CTE) *

(PSP) *

(CBD) *

Frontotemporal dementia and parkinsonism linked to chromosome 17 Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative tauopathy and Parkinson plus syndrome. FTDP-17 is caused by mutations in the MAPT (microtubule associated protein tau) gene l ...

(FTDP-17) * Vacuolar tauopathy *

Lytico-bodig disease Lytico-Bodig (also Lytigo-bodig) disease, Guam disease, amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), and Western Pacific amyotrophic lateral sclerosis-parkinsonism-dementia complex is a rare, terminal neurodegenerative dis ...

(Parkinson-dementia complex of Guam) *

Ganglioglioma A ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults. They are mixed cell tumors containing both neural ganglionic cells and neural gli ...

and

gangliocytoma A ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults. They are mixed cell tumors containing both neural ganglionic cells and neural gli ...

Meningioangiomatosis Meningioangiomatosis is a rare disease and tauopathy of the brain. It is characterized by a benign lesion of the leptomeninges usually involving the cerebral cortex, and by leptomeningeal and meningovascular proliferation. Often the patient wi ...

Subacute sclerosing panencephalitis Subacute sclerosing panencephalitis (SSPE), also known as Dawson disease, is a rare form of progressive brain inflammation caused by a persistent infection with the measles virus. The condition primarily affects children, teens, and young adults ...

(SSPE) * As well as lead encephalopathy,

tuberous sclerosis Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combinatio ...

, pantothenate kinase-associated neurodegeneration, and lipofuscinosis

References

External links

{{Cytoskeletal defects Dementia Medical signs Histopathology Cytoskeletal defects