Mechanisms of tau-induced neurodegeneration

By K. Iqbal, Fei Liu, C. Gong, A. Alonso, I. Grundke‐Iqbal. Acta Neuropathologica, 2009

645 citations recorded by the source corpus.

Alzheimer disease (AD) and related tauopathies are histopathologically characterized by a specific type of slow and progressive neurodegeneration, which involves the abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. This hallmark, called neurofibrillary degeneration, is seen as neurofibrillary tangles, neuropil threads, and dystrophic neurites and is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the non-fibrillized, abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau, which can be generated by catalysis of several different combinations of protein kinases, also promotes its misfolding, decrease in turnover, and self-assembly into tangles of paired helical and or straight filaments. Some of the abnormally hyperphosphorylated tau ends up both amino and C-terminally truncated. Disruption of microtubules by the non-fibrillized abnormally hyperphosphorylated tau as well as its aggregation as neurofibrillary tangles probably impair axoplasmic flow and lead to slow progressive retrograde degeneration and loss of connectivity of the affected neurons. Among the phosphatases, which regulate the phosphorylation of tau, protein phosphatase-2A (PP2A), the activity of which is down-regulated in AD brain, is by far the major enzyme. The two inhibitors of PP-2A, I1PP2A and I2PP2A, which are overexpressed in AD, might be responsible for the decreased phosphatase activity. AD is multifactorial and heterogeneous and involves more than one etiopathogenic mechanism.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/3eaae6e253b20336b93283c14ffb7b304651b0c3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. E. Mandelkow

In Molecular Biology

1. K. Del Tredici
2. Fei Liu
3. C. Gong
4. H. Braak
5. I. Grundke‐Iqbal
6. Urmi Sengupta
7. Yan Zhao
8. Baolu Zhao

In Physiology

1. K. Del Tredici
2. Fei Liu
3. C. Gong
4. H. Braak
5. E. Mandelkow
6. I. Grundke‐Iqbal
7. Urmi Sengupta
8. Yan Zhao

Citations in the corpus

• Oxidative Stress and the Pathogenesis of Alzheimer's Disease (2013, background): “Abnormal hyperphosphorylation of tau impairs its binding with tubulin and its capacity to promote microtubule assembly, resulting in its self-aggregation into filaments [118].”
• Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice (2011, background): “Although the importance of tau in AD and other tauopathies is well-established [ 5-7 ], unanswered is whether NFTs are the primary neurotoxic factor.”
• The pathological process underlying Alzheimer’s disease in individuals under thirty (2011, background): “In addition, according to the tau-microtubule hypothesis, it has been argued that soluble hyperphosphorylated tau is in itself highly toxic and incompatible with physiological cell functioning, whereas a better compatibility for the insoluble neurofibrillary lesions purportedly exists [2, 22, 53 , ”
• Post-translational modifications of tau protein: implications for Alzheimer's disease. (2011, neutral): “Although CDK5 regulates APP (amyloid precursor protein) processing and tau hyperphosphorylation, its involvement in AD remains controversial (Iqbal et al., 2009; Kerokoski et al., 2001; Lopes et al., 2010; Van den Haute et al., 2001).”
• Biochemistry and cell biology of tau protein in neurofibrillary degeneration. (2012, background): “A number of excellent reviews on the biology and pathology of Tau have appeared over the past few years (Cassimeris and Spittle 2001; Garcia and Cleveland 2001; Terwel et al. 2002; Dehmelt and Halpain 2005; Andreadis 2006; Ballatore et al. 2007; Gotz et al. 2007, 2010; Iqbal and Grundke-Iqbal 2008; ”
• Tau in Alzheimer Disease and Related Tauopathies (2010, background): “Studies on the role of tau in neurodegeneration and therapeutic targets based on this pathology have been the subject of several recent reviews by us and others [9-17].”