This Review summarizes our current understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease and related disorders. It is believed that tau-mediated neurodegeneration might result from a combination of a loss of normal tau function (primarily the microtubule (MT)-stabilizing function of tau) with gains of pathological functions of hyperphosphorylated tau, and the filaments formed thereof.
The primary function of tau is to stabilize the MTs. Under physiological conditions tau is in a tightly regulated dynamic equilibrium both on and off the MTs. This equilibrium, which is post-translationally regulated primarily by the phosphorylation state of tau, is thought to have a central role in maintaining effective axonal transport.
Under pathological conditions, an excessive disengagement of tau from the MTs takes place. This abnormal disengagement is likely to cause axonal transport defects. Furthermore, the increased cytosolic concentration of unbound tau renders the tau more likely to undergo misfolding and aggregation.
The aggregation of tau, leading to the formation of neurofibrillary tangles (NFTs), is likely to be associated with toxic gains-of-function. For example, NFTs may contribute to disease progression by further sequestering functional tau, thereby amplifying the loss of normal tau function. At the same time, relatively large NFTs may represent a direct physical obstacle to vesicles and other cargoes moving along the axons.
Direct causes of the pathological disengagement of tau from the MTs include tau gene mutations and an imbalance between tau kinases and phosphatases. Other pathological events, such as Aβ-mediated neurotoxicity, oxidative stress and inflammation, may also be able to initiate or contribute directly or indirectly to tau mediated neurodegeneration; however, their precise positioning in the cascade of events that leads to neuronal loss remains unclear.
A schematic overview of the various tau-directed therapeutic approaches currently under investigation is provided, along with an overview of the different transgenic mouse models that are available.
Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
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We thank our colleagues for their contributions to the work summarized here, which has been supported by grants from the US National Institutes of Health (P01 AG09215, P30 AG10124, P01 AG11542, P01 AG14382, P01 AG14449, P01 AG17586, PO1 AG19724, P01 NS-044233, UO1 AG24904), and the Marian S. Ware Alzheimer Program. Finally, we are indebted to our patients and their families, whose commitment to research has made our work possible.
The authors declare no competing financial interests.
- Senile plaque
A site of Aβ accumulation and dystrophic neurites in the brains of mouse models and patients with Alzheimer's disease.
- Alternative splicing
The process by which introns are excised from RNA after transcription and the cut ends of the RNA are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.
- Oxidative stress
A disturbance in the pro-oxidant-antioxidant balance in favour of the pro-oxidant, leading to potential cellular damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation and lipid peroxidation products.
- Dystrophic neurites
The processes (axons and dendrites) of neurons that are damaged or degenerating in AD.
A non-neuronal cell type that is present in the spinal cord and the brain (it is the resident CNS macrophage) and is characterized by its ramified morphology.
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Ballatore, C., Lee, V. & Trojanowski, J. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 8, 663–672 (2007). https://doi.org/10.1038/nrn2194
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