Neurobiology of tau protein: regulation and deregulation in vivo

Alzheimer’s disease (AD) is the leading form of dementia. The neuropathological hallmarks of Alzheimer’s disease include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP), and neurofibrillary tangles (NFT) of hyperphosphorylated tau protein assembled in paired helical filaments (PHF). NFT pathology is important, since it correlates with the degree of cognitive impairment in AD. Our laboratory focuses on understanding the causes and consequences of tau pathology.

We focus on 3 main research directions, performed mainly in vivo, with the help of transgenic mouse models of AD:

Molecular basis of tau regulation in vivo
Hyperphosphorylation of tau by deregulation of kinases and/or phosphatases has been proposed to dissociate tau from microtubules (MTs), thereby destabilizing the MTs and disrupting MT dependent axonal transport. Thus, we are studying the regulation of tau phosphorylation, tau splicing, and of tau toxicity and aggregation.
Impact of biological and environmental factors on AD pathogenesis
Only a small proportion of AD is due to genetic variants, the large majority of cases (~95%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Here, we study the impact of genetic and biological susceptibilities such as aging, diabetes, inflammation, and external factors, such as anesthesia and trauma, on the development of tau pathology.
Pharmacological treatments of AD pathology
Targeting tauopathy with pharmacological compounds to alleviate the symptoms of AD is a growing field of research. We have been conducting research studying the impact of kinase inhibitors, as well as MT stabilizing drugs on tau pathology in vivo. We have now developed collaborations to study the effects of new compounds, and new therapeutic approaches.
All our research would not be possible without the support and generosity of the Alzheimer’s Society of Canada, the CIHR, the NSERC, the FRSQ, the RQRV, and AFIRMAQ.

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Tatebayashi Y, Planel E, Chui DH, Sato S, Miyasaka T, Sahara N, Murayama M, Kikuchi N, Yoshioka K, Rivka R, Takashima A

c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis

Journal Article

FASEB J, 20 (6), 2006.

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Duff K, Planel E

Untangling memory deficits

Journal Article

Nat Med, 11 (8), 2005.

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Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo

Journal Article

Proc Natl Acad Sci U S A, 102 (19), 2005.

Abstract | Links:

Tatebayashi Y, Sato S, Akagi T, Chui DH, Miyasaka T, Planel E, Murayama M, Takashima A

Deregulation of GSK-3beta and JNK in a Mouse Model of Tauopathy: A Kinase Combination That Induces Alzheimer-Type Tau Hyperphosphorylation

Book Chapter

Takeda M, Tanaka T, Cacabelos R (Ed.): Molecular neurobiology of Alzheimer disease and related disorders, pp. 62-70, Basel, Karger, 2004, ISBN: 380557603X.

Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A

Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease

Journal Article

J Neurosci, 24 (10), 2004.

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Hatakeyama S, Matsumoto M, Kamura T, Murayama M, Chui DH, Planel E, Takahashi R, Nakayama KI, Takashima A

U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy

Journal Article

J Neurochem, 91 (2), 2004.

Abstract | Links:

Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A

Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau

Journal Article

Proc Natl Acad Sci U S A, 99 (21), 2002.

Abstract | Links:

Sato S, Tatebayashi Y, Akagi T, Chui DH, Murayama M, Miyasaka T, Planel E, Tanemura K, Sun X, Hashikawa T, Yoshioka K, Ishiguro K, Takashima A

Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells

Journal Article

J Biol Chem, 277 (44), 2002.

Abstract | Links:

Planel E, Yasutake K, Fujita SC, Ishiguro K

Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse

Journal Article

J Biol Chem, 276 (36), 2001.

Abstract | Links:

Yanagisawa M, Planel E, Ishiguro K, Fujita SC

Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease

Journal Article

FEBS Lett, 461 (3), 1999.

Abstract | Links:

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Active projects

  • Mechanisms of neuronal and vascular impairments in ischemic retinopathies, from 2019-04-01 to 2024-03-31
  • Microglial tau: a missing link between neuroinflammation and neurodegeneration in TDP-43 proteinopathies, from 2023-04-01 to 2028-03-31
  • Physiological regulation of tau protein, from 2023-04-01 to 2028-03-31
  • Prize - Mid Career Investigator Prize in Research in Aging: Microglial tau: a missing link between neuroinflammation and neurodegeneration in TDP-43 proteinopathies, from 2023-03-01 to 2024-02-29
  • Untangling tau contribution to cognitive impairments in Huntington’s disease., from 2019-04-01 to 2024-03-31

Recently finished projects

  • Neurobiologie de la protéine tau: régulation et dérégulation in vivo, from 2018-07-01 to 2022-06-30
  • Regulation of tau phosphorylation and splicing during post-embryonic development., from 2016-04-01 to 2022-03-31
  • Targeting tau pathology by modulating temperature, from 2018-07-01 to 2022-09-30
Data provided by the Université Laval research projects registery