Signaling pathway cross talk in Alzheimer's disease

Abstract

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

Figure 1

Hallmarks of AD, progression of the disease and mitochondrial dysfunction. A: The diagram shows the hallmarks in AD. B: The multiple pathogenic mechanisms contributing to the pathological hallmarks of AD consist of increased of ROS production, Aβ-induced mitochondrial dysfunction, and apoptosis due to impairment of mitochondrial Ca²⁺ handling ability, altered Ca²⁺ homeostasis, increased mitochondrial permeability transition pore opening, and promotion of cytochrome c release. Aβ inhibits protein import inside the mitochondria. APP also alters Ca²⁺ homeostasis leading to apoptosis. Mitochondrial DNA mutations and mitochondrial DNA damage are also involved in the pathogenesis of AD, and are associated with synaptic and neuronal loss, amyloid plaques, and NFTs. Perturbed cerebral energy metabolism plays a central role in multiple pathogenic cascades of AD. Abbreviations: AD, Alzheimer’s disease; Ca²⁺, calcium; Mptp, mitochondrial permeability transition pore; ROS, reactive oxygen species.

Figure 2

Interplay between Wnt signaling and other anti-ageing pathways. In this scheme we show the integration and interaction of multiple signaling pathways: the first line (top) shows a Wnt ligand, binding Frizzled receptor and activated canonical and non-canonical Wnt signaling. The canonical pathway (left) leads to GSK3β inhibition. AMPK activation is known to inhibit by GSK3β. The non-canonical pathway (right) increases intracellular Ca²⁺ levels. Nitric oxide (NO), a second messenger, is known to directly activate AMPK. AMPK is also activated by Ca²⁺ through CaMKK2. Therefore, AMPK activation by the Wnt pathway represents a hypothetical concept (“theoretical model” in transparent gray box). In the second line, AMPK leads to activation of Sirt1 (right). Sirt1 de-acetylates PGC-1α, and this transcription factor translocates to the nucleus and interacts with PPARγ heterodimerization to enhance the expression of mitochondrial biogenesis genes. As well, AMPK inhibits mTOR complex (right) resulting in autophagy stimulation. Additionally, we show the established target of several compounds (Li⁺, Metformin, Rapamicin, Resveratrol and Thiazolidinediones) on these intricate inter-linking signaling pathways to neuronal energy availability and cellular life span. Abbreviations: G, G-protein-coupled receptor; Dvl, Segment polarity protein disheveled homolog DVL-1; APC, adenomatous polyposis coli protein; Ca²⁺, calcium; Ca²⁺/CaM-dependent protein kinase kinase β (CaMKKβ); AMPK, 5' adenosine monophosphate-activated protein kinase; mTOR, mechanistic target of rapamycin, Sirt1, silent mating-type information regulator 2 homolog 1; PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1-α; GSK-3β, Glycogen synthase kinase 3; P,PPARα, phosphorylation; peroxisome proliferator-activated receptor alpha; Li⁺; lithium.