Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their τ isoform distribution and phosphorylation

Abstract

Aggregated tau proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two-dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease-specific tau protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological tau proteins (PTPs) (tau 74, 69, 64, 55) were compared with those of Pick's disease (PiD) (tau 64, 55) using a panel of antibodies against peptidic sequences of tau isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated tau isoforms with exon 10 in PiD PTPs, along with the absence of the phosphorylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti-"exon 2" antibody but failed to reveal any anti-exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of 7 isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific tau isoform patterns.

Tau Isoform Composition Influences Rate and Extent of Filament Formation

“…In myotonic dystrophy, 3R aggregation reflects primarily an abnormal MAPT expression pattern favoring exclusion of exons 2, 3, and 10 (62). In contrast, 3R aggregation in Pick disease occurs in certain cell populations (63), perhaps reflecting selective vulnerability of cells expressing primarily 3R Tau (e.g. neural precursor cells (64)).…”

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…However, the ability of intronic mutations to induce dominant familial tauopathy syndromes by creating an imbalance between three and four-repeat tau isoforms [70][71][72] also demonstrated that tau toxicity is dependent on an extremely subtle interplay between the parameters associated with MT:tau binding, tau:tau binding, and tau hyperphosphorylation.…”

La maladie d’Alzheimer : une tauopathie parmi d’autres ?

“…Cependant, Les corps de Pick sont localisés principalement dans les couches II et VI de l'isocortex et les neurones granulaires du gyrus denté. Ces neurones ne contiennent pas les isoformes 10+ de protéines tau [16]. Or, seules les isoformes de protéines tau hyperphosphorylées dépour-vues de la séquence codée par l'exon 10 (3R) présentent un tel profil électrophorétique [15,17].…”

“…Il est donc clair que des isoformes ne comportant pas cette séquence s'agrègent au sein des corps de Pick ( Figure 5). De plus, certains sites (KXGS), tels que les résidus Ser262 et 356, ne sont pas phosphorylés, suggérant l'absence ou l'inactivation des kinases impliquées dans cette phosphorylation, ou encore un problème d'accessibilité à ces sites [15,16]. Le profil électrophorétique des protéines tau permet donc de différencier certaines maladies neurodégéné-ratives.…”