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.

Synthetic and Natural Bioactive Molecules in Balancing the Crosstalk among Common Signaling Pathways in Alzheimer’s Disease: Understanding the Neurotoxic Mechanisms for Therapeutic Intervention

“…To sustain the electrochemical gradient, the mitochondria’s proper physiological activity relies on their intact structure. Several signaling pathways have been discovered using genetic methods as important mediators of the complex functionality of these neurons, deciding the execution of a process by their intraneuronal communications . Wnt signaling pathways, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and activation of the silent mating-type information regulator 2 homologue 1 (sirtuin 1) axis are among these signaling pathways (Figure ).…”

“…Several signaling pathways have been discovered using genetic methods as important mediators of the complex functionality of these neurons, deciding the execution of a process by their intraneuronal communications. 8 Wnt signaling pathways, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and activation of the silent mating-type information regulator 2 homologue 1 (sirtuin 1) axis are among these signaling pathways ( Figure 1 ). Figure 1 also depicts how the Wnt signaling pathway interacts with AMPK, Sirt1, PGC-1α, mTOR, and peroxisome proliferator-activated receptor gamma (PPAR-γ) that leads to a collective decision, either cell rescue or cell death.…”

Parallel molecular alteration between Alzheimer’s disease and major depressive disorder in the human brain dorsolateral prefrontal cortex: an insight from gene expression and methylation profile analyses

“…It has been reported that the progression of AD is associated with the formation of amyloid plaques and neurofibrillary tangles in the brain (Busciglio et al, 1997;Hooshmand et al, 2021). Also, the related signaling pathways in AD include Ras/ERK, PI3K/Akt and PKA/cAMP (Mizuno et al, 2012;Van Dooren et al, 2014).…”

A metabolic profiling approach to an Italian sage leaf extract (SoA541) defines its antioxidant and anti-acetylcholinesterase properties

“…A wide variety of AD risk factors have been identified but their role in onset and/or progression of the neuronal degeneration remains elusive. In other words, a coherent picture encompassing AD pathology, due to its multiple etiological factors (genetics, environmental factors and, in general, lifestyle), is still in its infancy (Van Dooren, Princen, De Witte, & Griffioen, 2014). Thus, discovering new treatments to prevent the disease is the challenge in AD research today.…”