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

Figure 1

APP, its processing products and TAU are part of an intraneuronal signalling network required for neurogenesis, neuronal function, and survival which go awry in AD. Aβo and AD risk factors modulate receptor mediated intraneuronal signalling and endocytosis which impacts Aβ homeostasis and TAU-phosphorylation. TAU-hyperphosphorylation leads to decreased microtubule binding, somatodendritic redistribution, and altered signalling. Apart from a modulatory role of Aβo, AICD, and phosphorylated TAU on signalling, their formation is also controlled by signalling implying a positive feedback loop which could overtime lead to a dysfunction of signalling cascades underlying synaptic integrity and neuronal survival. High levels of Aβo and hyperphosphorylated-TAU species will, due to their intrinsic amyloidogenic propensity, ultimately aggregate into plaques and tangles. Risk factors which impact these signalling processes, either directly or indirectly (i.e., through impacting Aβo levels), will set off this cascade of events culminating in synaptotoxicity and pathology. Note that the schematic is highly simplified and intended to depict general principles. For a more exhaustive insight into the signalling pathways impacted in AD, see [30]. Abbreviations are as follows: LDLR: low density lipoprotein receptor; IR: insulin receptor; IGF-R: insulin-like growth factor receptor; nACHR: nicotinic acetylcholine receptor; NMDAR: N-methyl-D-aspartate receptor; NGF-R: nerve growth factor receptor; Wnt: Wingless Int; PrPc: cellular prion protein; RAS: rat sarcoma; cAMP: cyclic adenosine monophosphate; PI: phosphoinositides; DAG: 1,2-diacylglycerol; mGluR5: metabotropic glutamate receptor; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; CamKK2: calcium/calmodulin-dependent protein kinase 2; and NFAT: nuclear factor of activated T-cells.