Centre Broca Nouvelle-Aquitaine and via Zoom
Physiological and pathological roles of the amyloid precursor protein at the presynapse.
Thesis supervisor: Gaël Barthet
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease which affects 47 million people worldwide, being the most prominent type of dementia. The etiology of the disease is unknown but genetic evidence from the familial form of the disease indicates that the amyloid precursor protein (APP) plays a key role in the pathology. The aim of my thesis was to study the physiological and pathological functions of APP related to its location at the presynapse. I studied the consequences on presynaptic mechanisms of the genetic deletion of APP and presenilin, the catalytic subunit of γ-secretase and intramembrane protease which cleaves APP. I then investigated possible alterations of APP, other than the amyloid peptides in AD brain, discovering that APP dramatically accumulates together with presynaptic proteins around dense-core amyloid plaques in human AD brain. Altogether, the data I collected during my thesis supports a role of presynaptic APP in physiology and in AD pathology and highlights APP accumulations as a pathological site where presynaptic proteins are mis-distributed.
Publications
Under review: APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brain
Tomàs Jordà-Siquier, Melina Petrel, Vladimir Kouskoff, Fabrice Cordelières, Susanne Frykman, Ulrike Müller, Christophe Mulle, Gaël Barthet
doi: https://doi.org/10.1101/2020.10.16.342196
Under review: Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer’s disease
Tomás Jordá-Siquier, Hazal Haytural, Bengt Winblad, Christophe Mulle, Lars O. Tjernberg, Ann-Charlotte Granholm, Susanne Frykman, Gaël Barthet
doi: https://doi.org/10.1101/2020.10.06.327833
Haytural H, Lundgren JL, Köse TB, Jordà-Siquier T, Kalcheva M, Seed Ahmed M, Winblad B, Sundström E, Barthet G, Tjernberg LO, Frykman S. Non-specific Detection of a Major Western Blotting Band in Human Brain Homogenates by a Multitude of Amyloid Precursor Protein Antibodies. Front Aging Neurosci. 2019 Oct 9;11:273
Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity
Barthet G, Jordà-Siquier T, Rumi-Masante J, Bernadou F, Müller U, Mulle C. . Nat Commun. 2018 Nov 14;9(1):4780.
Jury
Frederic Checler
Jochen Herms
Antonia Gutierrez
Eniko Kovari
Tomas Jordà-Siquier
Team Mulle
IINS