The Role of Tau
The “Tangles” Pathway
The “tangles” component of the classic Alzheimer’s disease “plaques and tangles” pathology may be critical to developing the first drug to alter the progression of Alzheimer’s disease and other neurodegenerative diseases like PSP where tangles are also found.
Neurofibrillary tangles are the result of degeneration of microtubules, key components of the communication and transport pathways inside brain cells (neurons). Tangles occur when tau protein, which normally helps bind microtubules together, converts from a soluble to an insoluble form, a process known as hyperphosphorylation. Aggregates of tau, such as tangles, are found in the brains of many types of neurodegenerative diseases such as progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD), and these diseases are collectively referred to as “tauopathies”.
Tau is implicated in many neurodegenerative diseases. Data from animal models of disease generated with Allon Therapeutics’ drug davunetide show a reduction of tau phosphorylation concurrent with improved cognition. Furthermore, Allon has shown a positive effect of davunetide in a Phase 2a human clinical trial where two daily 15 mg doses of davunetide over 12 weeks of treatment resulted in statistically significant, dose-dependent and durable improvements on two types of memory, specifically short-term recall and working memory. These two types of memory (also clinically relevant in Alzheimer’s disease) are thought to result from a build-up of tau tangles in these subjects. In fact, in amnesic mild cognitive impairment (aMCI) patients, memory loss is most closely linked to the build-up of tangles rather than plaques (2. Markesbery et al, 2006; 3. Petersen et al, 2006).
Microtubules and tau play a number of critical roles in normal neuron function
The primary function of tau is to stabilize microtubules. With its ability to modulate microtubule dynamics, tau directly or indirectly influences critical cellular functions. For example, the action of tau on stability of the microtubule network is a key factor in maintaining the appropriate structure of neurons, of which the axons and processes typically extend over significant distances. Furthermore, the microtubule skeleton allows appropriate transport of signaling molecules, trophic factors and other essential cellular constituents, including organelles (for example, mitochondria and vesicles) along the axons (axonal transport). The presence of tau on microtubules has significant effects on axonal transport and, hence, on the function and viability of neurons. (4. Ballatore et al, 2007)
Neurofibrillary tangles occur when the cytoskeleton of neurons collapses
In healthy neurons, tau binds to microtubules and stabilizes neuronal structure and function. Regulation of this complex structural network can go awry in several pathological conditions, like PSP and AD, resulting in deposition of paired-helical fragments of tau and eventually larger aggregates known as neurofibrillary tangles (4. Ballatore et al, 2007). These tangles are formed when tau dissociates from microtubules and clusters to form an insoluble mass containing hyperphosphorylated tau.
Hyperphosphorylation makes tau dissociate from microtubules, leading to tangles
The activity of tau and its binding to microtubules is controlled by a number of factors, the foremost of which is phosphorylation (the addition of a phosphate group to specific amino acids in the tau protein). Phosphorylation occurs on a number of different parts of the protein and an increase in phosphorylation generally reduces tau binding to microtubules. In AD, extremely high levels of phosphorylation are seen (hyperphosphorylation) and can be used as a marker for progression to AD. It is the hyperphosphorylation of tau that transforms it from its normal function towards an abnormal pathological role.
Formation of tangles results in loss of microtubule/tau function and appearance of toxic species
The loss of tau from microtubules has dual effects, both of which lead to neuronal dysfunction and ultimately cell death: 1) the loss of tau reduces microtubule integrity and reduces cell viability, and 2) tau forms into aggregates and tangles that are toxic to the neurons. In this way, a lack of proper tau control leads to both loss of microtubule function and an increased toxic insult, both of which lead to cell death.
Neurofibrillary tangles are evident in the brains of PSP, MCI and AD patients and correlate with cognitive loss
In PSP patients, large numbers of tau tangles are found in the areas of brain degeneration (Burn and Lees, 2007) and these areas of brain loss directly relate to disease progression (Paviour et al. 2006). Regional mapping of the areas of tangle build up suggest that it is the tau protein deposits in the frontal cortex basal ganglia and brain stem that is responsible for both the movement and cognitive deficits seen in these patients (Bak, 2011). Markesbery et al. (2006) found that neurofibrillary tangles were significantly elevated in all four ventromedial temporal lobe structures in patients with mild cognitive impairment (MCI) patients and early AD compared to subjects with normal cognition. This comparison revealed a relative increase of tangles in frontal and temporal lobes, amygdala and subiculum in the MCI and AD patients. The change in cognitive memory performance in normal subjects, MCI and early AD patients appeared to correlate with tangles in the hippocampal CA1 region and the entorhinal cortex. A study by Petersen et al. (2006) independently found that tangles correlated best with the degree of clinical impairment in aMCI patients, and the brain structure most affected was the medial temporal lobe structure which may account for memory impairment.
Neurofibrillary tangles can cause neurodegeneration in the absence of plaques
A number of neurodegenerative disorders, known collectively as tauopathies, show a build-up of tangles in the absence of amyloid plaques. These conditions (including PSP, Pick’s disease and frontotemporal dementia) show a progressive accumulation of filamentous tau aggregates leading to brain dysfunction and degeneration (5. Lee et al, Ann Rev Neurosci, 2001). Tangles are therefore a critical element of neurodegeneration in various conditions, including AD and those where amyloid beta plays no role.