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Séminaire - Ulrike Müller "The APP gene family: from physiological functions to new therapeutic concepts".

Abstract :


 The amyloid precursor protein APP plays a key role in the pathogenesis of Alzheimer’s disease (AD), as proteolytical cleavage of APP gives rise to the Aβ peptide which is deposited in the brains of Alzheimer patients.
Despite this, our knowledge of the normal cell biological and physiological functions of APP and the closely related APLPs is limited. This may have hampered our understanding of AD, since evidence has accumulated that not only the production of the Aβ peptide but also the loss of APP-mediated functions may contribute to AD pathogenesis. Why is our understanding of the APP functions so limited? APP and the APLPs are multifunctional proteins that undergo complex proteolytical processing.
They give rise to an almost bewildering array of different fragments that may each subserve specific functions. While Aβ is aggregation prone and neurotoxic, the large secreted ectodomain APPsα - produced in the non-amyloidogenic α-secretase pathway - has been shown to be neurotrophic, neuroprotective and relevant for synaptic plasticity, learning and memory. Recently, novel APP cleavage pathways and enzymes have been discovered that have gained much attention not only with respect to AD but also regarding their role in normal brain physiology. In addition to the various cleavage products, there is also solid evidence that APP family proteins mediate important functions as transmembrane cell surface molecules, most notably in synaptic adhesion and cell surface signaling.
To elucidate the different aspects of APP function in particular at the synapse we have developped several conditional knockout mice ans well as mouse mutants lacking specific APP domains. In addition we have recently demonstrated the therapeutic potential of APPsα in transgenic Alzheimer model mice.
http://www.ipmb.uni-heidelberg.de/bioinfo-fkt_gen/mueller/

Selected publications

Fol R, Braudeau J, Ludewig S, Abel T, Weyer SW, Roederer JP, Brod F, Audrain M, Bemelmans AP, Buchholz CJ, Korte M, Cartier N, Müller UC (2016) Viral gene transfer of APPsalpha rescues synaptic failure in an Alzheimer's disease mouse model. Acta Neuropathol 131: 247-266

Hick M, Herrmann U, Weyer SW, Mallm JP, Tschape JA, Borgers M, Mercken M, Roth FC, Draguhn A, Slomianka L, Wolfer DP, Korte M, Müller UC (2015) Acute function of secreted amyloid precursor protein fragment APPsalpha in synaptic plasticity. Acta Neuropathol 129: 21-37

Klevanski M, Herrmann U, Weyer SW, Fol R, Cartier N, Wolfer DP, Caldwell JH, Korte M, Müller UC (2015) The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. J Neurosci 35: 16018-16033

Weyer SW, Klevanski M, Delekate A, Voikar V, Aydin D, Hick M, Filippov M, Drost N, Schaller KL, Saar M, Vogt MA, Gass P, Samanta A, Jaschke A, Korte M, Wolfer DP, Caldwell JH, Müller UC (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30: 2266-2280

Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T, Müller UC (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsalpha expression. Acta Neuropathol Commun 2: 36

Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A, Hampel H, Muller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller UC, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C (2015) eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526: 443-447