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Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer’s disease

From Unité Inserm 422 (Drs. Delacourte, Sergeant, and David, and A. Wattez), Lille; and CH&U, EA2691, and ADERMA (Drs. Maurage, Lebert, and Pasquier), Salengro Hospital, Lille, France.

Address correspondence and reprint requests to Dr. A. Delacourte, Unité Inserm 422, 1, Place de Verdun, 59045 Lille Cedex, France; e-mail: delacourte{at}lille.inserm.fr

Objective: To determine the spatiotemporal mapping of tau pathologies and insoluble pools of Aß in aging and sporadic AD, and their contribution to the physiopathologic, clinical, and neuropathologic features.

Methods: The authors studied 130 patients of various ages and different cognitive status, from nondemented controls (n = 60) to patients with severe definite AD (n = 70) who were followed prospectively. Insoluble Aß 42 and 40 species were fully solubilized and quantified in the main neocortical areas, with a new procedure adapted to human brain tissue. Tau pathology staging was determined in 10 different brain areas, using Western blots.

Results: In AD, there is a constellation of amyloid phenotypes, extending from cases with exclusively aggregated Aß 42 to cases with, in addition, large quantities of insoluble Aß 40 species. Five other points were observed: 1) There was no spatial and temporal overlap in the distribution of these two insoluble Aß species in cortical brain areas. 2) In contrast to solubilized Aß 40 aggregates composed essentially of monomers and dimers, solubilized Aß 42 was essentially observed as dimers and multimers. 3) Aß 42 aggregates were observed at the early stages of tau pathology, whereas the insoluble Aß 40 pool was found at the last stages. 4) During the progression of the disease, Aß aggregates increase in quantity and heterogeneity, in close parallel to the extension of tau pathology. 5) There was no spatial overlap between Aß aggregation that is widespread and heterogeneously distributed in cortical areas and tau pathology that is progressing sequentially, stereotypically, and hierarchically.

Conclusions: These observations demonstrate that Aß 42 aggregation, and not Aß 40, is the marker that is close to Alzheimer etiology. It should be the main target for the early biological diagnosis of AD and modeling. Furthermore, the spatial mismatch between amyloid ß-precursor protein (APP) and tau pathologies in cortical brain areas demonstrates that neurodegeneration is not a direct consequence of extracellular Aß neurotoxicity. Hence, there is a synergetic effect of APP dysfunction, revealed by Aß aggregation, on the neuron-to-neuron propagation of tau pathology.

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