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BioMed Research International
Volume 2014 (2014), Article ID 167024, 14 pages
Review Article

Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer’s Disease

reMYND, Gaston Geenslaan 1, 3001 Leuven, Belgium

Received 9 May 2014; Revised 31 July 2014; Accepted 3 August 2014; Published 27 August 2014

Academic Editor: Yiying Zhang

Copyright © 2014 Tom Van Dooren et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.