title: Derailed intraneuronal signalling drives pathogenesis in sporadic and familial Alzheimer's disease.
abstract: Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively.
authors.affiliation: reMYND, Gaston Geenslaan 1, 3001 Leuven, Belgium.
authors.forename: Tom
authors.identifier: 0000-0002-3945-2130
authors.initials: T
authors.lastname: Van Dooren
authors.affiliation: reMYND, Gaston Geenslaan 1, 3001 Leuven, Belgium.
authors.forename: Katrien
authors.identifier: 0000-0002-7209-6422
authors.initials: K
authors.lastname: Princen
authors.affiliation: reMYND, Gaston Geenslaan 1, 3001 Leuven, Belgium.
authors.forename: Koen
authors.identifier: 0000-0002-1246-6217
authors.initials: K
authors.lastname: De Witte
authors.affiliation: reMYND, Gaston Geenslaan 1, 3001 Leuven, Belgium.
authors.forename: Gerard
authors.identifier: 0000-0003-2492-6046
authors.initials: G
authors.lastname: Griffioen
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004705:Endocytosis; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012307:Risk Factors; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins