Cited by 124Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets

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Lee, V. M.-Y., Brunden, K. R., Hutton, M., Trojanowski, J. Q.·2011·Cold Spring Harbor Perspectives in Medicine

Abstract

A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.

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Crossref · 10.1101/cshperspect.a006437

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  • Hyperphosphorylated tau has been shown to cause neuronal cell death in humans.

    “hyperphosphorylated tau has been shown to cause neuronal cell death (Lee et al., 2011)”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Lee et al., 2011

    The introductory discussion says altered tau can cause neurodegeneration and that tau hyperphosphorylation is observed in human disease. But it says the contribution of phosphorylation to the onset of tau pathology in Alzheimer’s disease remains uncertain; it does not establish that hyperphosphorylated tau causes neuronal cell death in humans. The cited review supports a link between tau changes and neurodegeneration, not the claim’s specific causal conclusion. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • Tauopathies including Alzheimer disease are characterized by progressive intracellular inclusions of the microtubule-stabilizing protein tau in affected brain regions.

    “are all characterized by the progressive development of intracellular inclusions of the microtubule-stabilizing protein tau in affected brain regions (1, 2).”
  • Dysregulated GSK3β is implicated in the pathogenesis of Alzheimer disease.

    “implicated in the pathogenesis of AD, and reducing its activity may have therapeutic efficacy (2).”

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Authors
Lee, V. M.-Y., Brunden, K. R., Hutton, M., & Trojanowski, J. Q.
Affiliations
  • University of Pennsylvania (US)
  • Eli Lilly (United States) (US)
Venue
Cold Spring Harbor Perspectives in Medicine
Published
2011-09-01
Volume
1
Issue
1
Pages
a006437-a006437
ISSN
2157-1422 (ISSN-L)
OpenAlex
W2137326161
Cited by
122
References
169
Citations by year
2026: 1 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 8 · 2017: 9 · 2016: 16 · 2015: 10 · 2014: 9 · 2013: 10 · 2012: 11
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AG 10 124, 5u01ag024904-10, AG-11542, P01 AG11542, P01 AG17586, NS044233, AG 17586, AG-09215, P01 AG09215, AG24904, AG19724, PO1 AG19724, AG14449, UO1 AG24904, AG14382, P01 AG14382)
  • National Institute on Aging (U01-AG-024904, P01AG014382, P01AG011542, P01AG014449, P30AG010124, P01AG009215, P01AG017586, P01AG019724)
  • National Institute of Neurological Disorders and Stroke (P01NS044233)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
tau protein, Alzheimer's disease, tau kinases, tau aggregation, tauopathy, frontotemporal lobar degeneration, gain-of-function toxicity, neurodegeneration
MeSH terms
Alzheimer Disease, Central Nervous System Agents, Genetic Markers, Humans, Phosphorylation, Biomarkers, Neurofibrillary Tangles, tau Proteins, Glycogen Synthase Kinase 3, Protein Kinase Inhibitors, Drug Discovery, Molecular Targeted Therapy

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