Hyperphosphorylated tau (p-tau) and drug discovery in the context of Alzheimer's disease and related tauopathies

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized by intracellular neurofibrillary tangles (NFTs) and extracellular β-amyloid (βA) plaques. No disease-modifying therapy is currently available to prevent the progression of, or cure, the disease. Misfolded hyperphosphorylated tau (p-tau) is considered a pivotal point in the pathogenesis of AD and other tauopathies. Compelling evidence suggests that it is a key driver of the accumulation of NFTs and can be directly correlated with the extent of dementia in patients with AD. Therefore, inhibiting tau hyperphosphorylation-induced aggregation could be a viable strategy to discover and develop therapeutics for patients with AD.

Keywords: Alzheimer’s; amyloid; dementia; hyperphosphorylation; tau; therapy.

Figure 1.

Statistical representation of the prevalence and prediction of dementia worldwide from 2017 to 2050. The y-axis represents the number of patients diagnosed with dementia in millions of people. The x-axis depicts four separate years of census; years 2015 and 2022 have recorded data, whereas years 2030 and 2050 are predictions based on information from WHO. The incidence of dementia is expected to increase nearly threefold by 2050 compared with 2015, as a result of an everincreasing aging population.

Figure 2.

Structure of tau protein and its domain organization. MAPT encodes six unique isoforms: isoforms with three repeating sites (pink) are depicted to the left, and isoforms with four repeating sites are on the right. The isoforms appear from top to bottom in order of length (number of amino acids), which is dictated by the number of N-domain sites (purple). Each isoform contains one proline-rich domain (green) and one C-terminal site (blue), which flank the repeating sites.

Figure 3.

Tau hyperphosphorylation and aggregation. The stabilized microtubule, represented in purple and teal, will inherently carry tau protein monomers (yellow circles). As phosphate molecules (pink letter ‘P’) approach, they bind to the tau protein in a process known as phosphorylation. The resulting hyperphosphorylated tau (p-tau) leads to destabilization of the microtubule. Following this step, p-tau monomers accumulate to form oligomers, which further congregate to form paired helical filaments (PHFs). These PHFs can be imagined as forming a patchwork to create neurofibrillary tangles (NFTs). These NFTs, located within the soma of affected neurons, are suspected to be the pathological feature of Alzheimer’s disease.

Figure 4.

One proposed theory for tau seeding and spreading via trans-synaptic transmission (among other possible routes). The large blue shapes represent neurons, whereas the pink circles are tau seeds. The flow of seeding is downwards in this figure. First, tau protein fibrils disassemble into individual seeds, which are expelled into the synaptic gap between neurons. The tau seeds can be free-floating or encased in a vesicle (depicted by a gray ring). As these tau seeds encounter another neuron, the neuron uptakes the tau, where they are strung together in a process known as seeding. Following this step, fibril growth can take place in the newly infected neuron. This diagram explains the spread of neurodegeneration through the brain at a molecular level.

Figure 5.

Therapeutic strategies targeting tau for the treatment of Alzheimer’s disease. These are six possibilities for disrupting the formation of tau aggregate. (1) Prevent tau phosphorylation and subsequent destabilization of the microtubule by prohibiting phosphate molecules from attaching to the tau protein monomers. (2) Stabilize microtubules, even with the presence of phosphorylated tau (p-tau) on the surface of the microtubule. (3) Clear p-tau to the extracellular space to move it away from the microtubule, ideally reverting destabilization. (4) Degradation of p-tau oligomers to prevent subsequent formation into higher-level aggregates. (5) Prevention of p-tau aggregation to prohibit formation of neurofibrillary tangles (NFTs) within neurons. This step can occur either before the creation of paired helical filaments (PHFs) or before the accumulation of NFTs. (6) Prevention of intercellular tau transfer and uptake to prevent neurons from being affected through the process of seeding.