Description

The normal physiological function of MAPT is believed to be the stabilization of microtubules. The protein provides stability by virtue of multiple microtubule-binding repeat sequences that vary in number depending on the MAPT isoform. Binding of MAPT promotes microtubules in their polymerized state and, thereby, facilitates axonal transport and maintains neuronal integrity (17). Grey matter expresses MAPT at higher concentrations than white matter or cerebellum. MAPT also has been found to have a physiologic role in dendrites and to be expressed in low levels in glial cells (15). There are six known isoforms of MAPT, and misfolding of certain isoforms can lead to differences in disease (17). The discovery of genetic mutations in MAPT confirmed the role of abnormal tau protein aggregation in the etiology of neurodegenerative diseases. As mentioned previously, PART can be pathologically identified in aging brains, with the most common tau inclusions identified as neurofibrillary tangles, threads, and argyrophilic grains (13).

Many pathologic processes have been implicated in the development of tauopathies. Both gain of function and loss of function processes have been identified, resulting in simultaneous loss of axonal transport capacity and a plethora of diverse toxic effects from aggregated proteins, including synaptic damage, reduced neuronal plasticity, microtubule destabilization, and, ultimately, neuronal death (21). Likely the most important process is hyperphosphorylation of tau protein, which causes an inability for the tau to interact with microtubules (17). It is believed that MAPT hyperphosphorylation leads to insolubility of the tau protein, which creates filaments that then aggregate in cells and exhibit direct toxic effects. While this process occurs sequentially, there is a long time lapse between the formation of aggregates in the cell and clinical symptoms (17). Evidence for MAPT as a mediator of cell death can be seen in the staging of tauopathies. The Braak rating scale for Alzheimer disease is based on the distribution of MAPT deposition and tracks well with clinical manifestations of the disease (04). McKee and colleagues proposed a similar rating scale for chronic traumatic encephalopathy (20), and studies have demonstrated the utility of the rating scale with the chronic traumatic encephalopathy stage strongly correlating with the degree of cognitive impairment (01). Similar findings have been reported for variants of progressive supranuclear palsy. Sakae and colleagues report increased frontal, temporal, and white matter MAPT pathology in patients with progressive supranuclear palsy with frontotemporal dementia compared to patients with progressive supranuclear palsy, referred to as Richardson syndrome (23).

In some tauopathies, specifically Alzheimer disease, chronic traumatic encephalopathy, and postencephalitis Parkinson disease, the tangles formed by aggregated filaments remain in the extracellular space following death of the affected cells (17). These “ghost tangles” may contribute to disease propagation throughout the brain by making MAPT accessible to other cells in the extracellular space. This is likely a critical aspect of the pathophysiology of tauopathies. Braak first identified that tau inclusions originated in the transentorhinal cortex in Alzheimer disease and then spread from there (04). Since then, numerous mouse studies have shown that injection of extracts with mutant MAPT into wild-type animals causes widespread induction of the pathologic protein into neighboring areas that then degenerated (26). Furthermore, injection into animal models of human brain tissue with different pathologic inclusions consistent with confirmed corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain disease produced lesions in the animal brains demonstrating the same pathologic and phenotypic disease as the respective tauopathy injected (17). This supports the theory of “prion-like” propagation throughout the brain and suggests distinct confirmations of MAPT for individual diseases (17). The presence of pathologic MAPT in the extracellular space is also confirmed by the ability to find MAPT in the cerebrospinal fluid of patients with tauopathies.

Data suggest that neurons are not the only cell types affected by abnormal MAPT. The potential role for glial cells in disease propagation was illustrated in a large study examining distribution patterns of aging-related tau astrogliopathy across several tauopathies (14). To develop a sequential staging format, the authors examined ARTAG in the brains from patients with Pick disease, progressive supranuclear palsy, and corticobasal degeneration. Unique pathways for grey matter ARTAG progression were uncovered across the diseases that were largely consistent with their known clinical progression. Similar to the processes identified in neurons, ARTAG has also been recognized in nondiseased aging brains (07). Cortical ARTAG was seen in 38% (117/310) of patients in a European community-based population (07). Interestingly, ARTAG has a similar anatomic distribution to chronic traumatic encephalopathy. Although the two may coexist, none of the patients with ARTAG in this study met the criteria for chronic traumatic encephalopathy (07). ARTAG pathologically does differ from the astrogliopathy identified in disease states. Thorn-shaped astrocytes with greater perinuclear cytoplasm and short, thick processes are found in perivascular, subpial, subependymal grey and white matter in the depths of the gyri, basal forebrain, and brainstem but largely spare the deep cortical layers (15). Additionally, a second pathologic characteristic of ARTAG is the presence of granular fuzzy astrocytes, which are characterized by fine granular tau deposits in the astrocyte processes within the gray matter. These two together form the pathologic definition of ARTAG and can be seen with or without other astrogliopathy signatures of neurodegeneration. It is yet to be determined the role ARTAG plays in pathologic tauopathies, but evidence suggests that, similar to PART, ARTAG may be a prodromal or early phase in primary tauopathies (13). The distribution of granular fuzzy astrocytes and thorn-shaped astrocytes in ARTAG may help to elucidate the role of astrogliopathy in the initiation of certain tauopathies, and more research is needed to fully understand the relationship between astrogliopathy and neuronal tauopathy in pathologic disease.

Other processes that may be implicated in the pathophysiology of tauopathies include mitopathy and neuroinflammation. Mitopathy is a process that has been implicated in early Alzheimer disease and involves mitochondrial dysfunction and autophagic-lysosomal alterations (10). These processes have been associated in animal studies with MAPT pathology, but the exact relationship is yet to be understood. Neuroinflammation likely has a contributory role in the neurodegenerative process with the simultaneous potential to be critically protective and potentially harmful. Supportive of this connection, a study demonstrated colocalization of radiolabeled markers of neuroinflammation and MAPT pathology in 17 patients with progressive supranuclear palsy (18). Even more compelling was the strong positive correlation between clinical severity and both subcortical neuroinflammation and MAPT pathology. Overall, the complex interplay between tau and other processes that lead to neurodegeneration is still being explored through animal models, neuropathologic studies, and clinical trials.

Clinical applications

Tauopathies are a group of more than 20 heterogeneous diseases characterized by the identification of tau inclusions in neurons or glia (09). They can be divided into primary tauopathies, which pathologically only have tau inclusions noted, and secondary tauopathies, which have tau in addition to other inclusions associated with disease progression. The primary tauopathies often fall under the category of frontotemporal lobar degeneration and include Pick disease, progressive supranuclear palsy, and corticobasal degeneration. Secondary tauopathies include Alzheimer disease, which, as described above, was the first tauopathy to be described and is the most common. Alzheimer disease is a secondary tauopathy due to the concurrent presence of beta-amyloid with MAPT inclusions as causative agents for degeneration. The most recently identified tauopathy is chronic traumatic encephalopathy, a disorder characterized by repetitive head trauma leading to the “accumulation of hyperphosphorylated tau in neurons and astroglia around small blood vessels at the depth of the cortical sulci and in an irregular pattern” (01). A full review of the clinical disorders of tauopathies is outside the scope of this article. Instead, developments in the identification and treatment of tauopathies based on the pathologic understanding of the disease are briefly reviewed below.

Biomarkers. For decades, confirmation of tau was limited to autopsy evaluation. In the past few years, PET imaging is emerging as a way to identify tau pathology in vivo by using radiolabeled ligands against neurofibrillary tangles containing tau (19). In Alzheimer disease, the radiolabeled ligand [18F]-AV-1451 or flortaucipir was shown to successfully identify tau distribution in patients compared to healthy controls, likely due to binding to the paired helical conformation of tau in Alzheimer disease brains. Yet in other tauopathies, the data for flortaucipir to identify tau in the expected areas have been variable, and off-target binding may limit its utility in chronic traumatic encephalopathy and other disorders. Several other ligands have also been created, and in mild traumatic brain injury and chronic traumatic encephalopathy, promising results suggest that tau can be successfully imaged in vivo. One such ligand, 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) was able to identify tau deposits in Alzheimer disease and non-Alzheimer disease tauopathies. This ligand also demonstrated increased MAPT-PET binding in the neocortical grey and white matter in patients with late-onset neuropsychiatric symptoms following traumatic brain injury (27). A particularly close correlation was found between psychosis and tracer binding in the white matter. One small study examined patients at risk for chronic traumatic encephalopathy and was able to demonstrate a tau-PET binding profile consistent with later-stage chronic traumatic encephalopathy in patients who were negative for amyloid-PET binding. The authors concluded that MAPT-PET binding may represent a useful biomarker for chronic traumatic encephalopathy but is currently only for later-stage disease (16). Similar results were shown in patients with progressive supranuclear palsy who demonstrated increased tau-PET binding in the globus pallidus and putamen relative to age-matched healthy controls (24). There was, however, a positive correlation between tau-PET binding and age within both groups, which may challenge the application and clinical utility of this technology as a diagnostic tool. Further studies were proposed to investigate whether tau-PET binding within the basal ganglia may have utility as a marker of progression in clinical trials for progressive supranuclear palsy.

Extracellular MAPT as measured in cerebrospinal fluid has potential as a biomarker of disease progression. By examining MAPT levels in CSF from patients with normal cognition (n=1111), mild cognitive impairment (n = 1213), and Alzheimer disease (n = 1524) from two independent cohorts, four subgroups were identified based on MAPT levels (06). Individuals with the highest amounts of MAPT in their CSF also displayed the most significant cognitive decline and were at the highest risk of progressing to Alzheimer disease. Curiously, an inverse correlation was found with CSF levels of phosphorylated MAPT and rates of progression in patients with progressive supranuclear palsy (22). The opposite associations between MAPT in CSF between progressive supranuclear palsy and Alzheimer disease may highlight pathophysiological differences between the conditions.

Disease-modifying therapies. Given the strong association between tau deposition, cellular toxicity, and neurodegeneration, MAPT is an obvious target for potential disease-modifying therapies. Immunotherapies are being employed to harness the immune system to prevent hyperphosphorylation of MAPT, stop filament formation, and clear the aggregates from the extracellular milieu, all in the hope of ultimately halting disease progression. Active and passive antibody-based clinical trials are underway or have been completed for Alzheimer disease and progressive supranuclear palsy. Two stage 1 studies with humanized monoclonal antibodies against MAPT demonstrated the treatments were well tolerated with no reported severe adverse effects (29; 03). Active vaccination against pathological tau is also being pursued with encouraging results (21). The FUNDAMANT trial was an open-label phase 1 clinical trial that followed 26 participants with mild to moderate Alzheimer disease in a 72-week study looking primarily at tolerability and response rate to a vaccination procedure against pathologic MAPT protein. The active vaccination was well tolerated, with no cases of vasogenic edema, meningoencephalitis, or other serious adverse effects. All responders retained an immunoglobulin response; however, booster doses were required to maintain titer levels. Although the results were preliminary, there was an encouraging trend toward slower hippocampal atrophy and reduced cognitive decline in those with the highest antibody titers (21).

Many treatment approaches that have shown promise in animal models of tauopathies have failed to prove safe and effective in human clinical trials. The vast majority of these trials are in Alzheimer disease and target microtubule stabilization, prevention of tau hyperphosphorylation, and reduction of tau aggregates. Valproic acid, lithium, methylene blue, and NAP failed to show cognitive improvement in randomized trials (02; 25). Most recently, Tsai and colleagues reported the results of a basket-designed randomized phase 1 clinical trial with TPI-287 or abeotaxane in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome (28). The safety profile revealed that patients with Alzheimer disease tolerated the drug poorly, with 3 of the 26 patients developing severe anaphylactoid reactions to the compound. This was not true with any of the 46 patients with progressive supranuclear palsy or corticobasal syndrome. However, the overall results showed more falls in the treated group and a dose-related worsening of dementia symptoms, leading to the discontinuation of the development of TPI-287. Although MAPT is an appealing and potentially promising target for disease-modifying therapy, more research is needed to find a safe treatment that slows cognitive decline in tauopathies.