Tauopathies are a group of devastating – and often fatal – neurodegenerative diseases characterized by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Accumulation of hyperphosphorylated tau in these regions causes the formation of neurofibrillary tangles that are characteristic of many neurodegenerative conditions including Alzheimer’s disease, frontotemporal lobar degeneration (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration. In the years since the initial discovery of these tangles, scientists have worked feverishly to connect the dots between tau dysfunction and neurodegeneration.
Research mostly focused on identifying the cause of abnormal tau phosphorylation and subsequent aggregation in hopes of someday developing effective therapeutic interventions for Alzheimer disease (AD) and realted tauopathies.
Involvement of Tau in Neurodegenerative Diseases
First described in 1907 by Alois Alzheimer, neurofibrillary tangles are a key pathological feature of many neurodegenerative diseases. Subsequent research revealed the main component of these tangles - a hyperphosphorylated, filamentous form of the tau protein.
Researchers subsequently discovered a group of inherited tauopathies, deemed FTD, caused by mutations in the tau gene (MAPT). Using this discovery, scientists could demonstrate that tau dysfunction can indeed drive neurogeneration.
Mechanisms of Tau Neurotoxicity
Hyperphosphorylated tau causes over-stabilization of actin filaments, resulting in excess F-actin that reduces localization of the protein DRP1. This prevents DRP1 from reaching the mitochondrial outer membrane when necessary to perform mitochondrial fission or to do routine maintenance. Neurons of mice and fruit flies (Drosphila melanogaster) that express too much wild type human tau or tau FTDP mutant actually have longer mitochondria resulting from this reduced localization of the DRP1 protein.
The 1964 study published in Brain revealed that brains affected by AD show abnormally shaped mitochondria in dystrophic neuritis. A 2006 study verified the presence of morphologically distorted mitochondria in AD brains.
As a highly-metabolic organ, the brain relies on proper mitochondrial function. A byproduct of mitochondrial function, including buffering calcium ion levels and providing energy to the cells in the form of ATP, is the formation of ROS (reactive oxygen species). ROS imbalances give rise to oxidative stress.
The nervous system is quite sensitive to oxidative stress. A June 2012 study shows that AD brains demonstrate clear evidence of oxidative stress. Animal models also show damage from free radicals and sensitivity to oxidative stress.
While scientists are still working to put together the final links, studies make it clear that reducing mitochondrial localization increases ROS and oxidative stress that, in turn, leads to DNA damage, abnormal cell cycles and apoptosis. Animal models do show increased ROS and apoptosis.
In various animal models, transgenic expression of mutant tau causes progressive neuronal death. These models helped researchers identify and characterize specific key cellular processes capable of promoting apoptosis associated with tauopathy, including:
- Synapse loss
- Impaired axonal transport
- Overstabilization of filamentous actin
- Mitochondrial dysfunction
- Oxidative stress
- DNA damage
- Epigenetic changes
- Aberrant cell cycle activation in postmitotic neurons
After decades of research, scientists now know a great deal about the specific sequence of events leading from tau dysfunction to neuronal death, but more work is necessary to come up with viable therapeutic strategies that target this pathway from dysfunction to death.
Physicians currently base treatment for AD, the most common tauopathy, on patient symptoms. Because tau pathology and severity of disease are closely associated, and the fact that tau acts downstream of amyloid b (Ab) to induce neuronal death, researchers now think tau-based therapies may effectively treat AD and other less common tauopathies. Current strategies focus on reducing tau aggregation, stopping tau hyperphosphorylation, and stopping or slowing the spread of tau pathology throughout the brain. Therapies aimed at eliminating hyperphosphorylated tau are of special interest. Genetic factors in the tau dysfunction to neuronal death pathway also present interesting targets for therapeutic intervention.
Researchers have made tremendous progress in identifying the underlying causes of cell death occurring subsequent to tau dysfunction. Reversing events in the pathway between tau dysfunction and apoptosis significantly reduces tau neurotoxicity in animal models. Each event in this cascade offers an opportunity for therapeutic intervention that treat tauopathies, including Alzheimer’s disease. For now, scientists continue their work to connect the dots between tau dysfunction and neurodegeneration.