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Cereb Cortex ; 28(11): 3976-3993, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-29048465

RESUMEN

The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-ß (Aß) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism. Here, we described that an AD-like ßAPP processing in adults wild-type rats, yielding to human APP, ßCTF and Aß levels similar to those observed in AD patients, is sufficient to trigger gradual Tauopathy. The Tau hyperphosphorylation begins several months before the formation of both amyloid plaques and tangle-like aggregates in aged rats and without associated inflammation. Based on a longitudinal characterization over 30 months, we showed that extrasynaptic and emotional impairments appear before long-term potentiation deficits and memory decline and so before Aß and Tau aggregations. These compelling data allowed us to (1) experimentally confirm the causal relationship between ßAPP processing and Tau pathology in vivo and without Tau transgene overexpression, (2) support the amyloidogenic cascade and (3) propose a 4-step hypothesis of prodromal AD progression.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Animales , Progresión de la Enfermedad , Femenino , Vectores Genéticos , Humanos , Potenciación a Largo Plazo , Masculino , Fragmentos de Péptidos/metabolismo , Placa Amiloide/metabolismo , Presenilina-1/genética , Agregación Patológica de Proteínas/metabolismo , Ratas Wistar
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