From tau phosphorylation to tau aggregation: what about neuronal death?
Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.
Buée
Luc
L
Inserm, U837, rue Polonovski, 59045 Lille, France. luc.buee@inserm.fr
Troquier
Laëtitia
L
Burnouf
Sylvie
S
Belarbi
Karim
K
Van der Jeugd
Anneke
A
Ahmed
Tariq
T
Fernandez-Gomez
Francisco
F
Caillierez
Raphaelle
R
Grosjean
Marie-Eve
ME
Begard
Séverine
S
Barbot
Bérangère
B
Demeyer
Dominique
D
Obriot
Hélène
H
Brion
Ingrid
I
Buée-Scherrer
Valérie
V
Maurage
Claude-Alain
CA
Balschun
Detlef
D
D'hooge
Rudi
R
Hamdane
Malika
M
Blum
David
D
Sergeant
Nicolas
N
D000818:Animals; D016923:Cell Death / Q000502:physiology; D011232:Chemical Precipitation; D004195:Disease Models, Animal; D006801:Humans; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D055503:Protein Multimerization / Q000502:physiology*; D024801:Tauopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D016875:tau Proteins; D011494:Protein Kinases