Alzheimer's Disease: An Update and Insights Into Pathophysiology

Abstract

Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD.

Keywords: Alzheimer; JAK; NGF; dementia; diagnose; omic; therapeutic; vascular.

FIGURE 1

Fibroblast growth factors (FGFs) bind to their receptors (FGFRs), activating their tyrosine kinase domain through phosphorylation. FGF/FGFR complex initiates the downstream signaling, by recruiting Growth factor receptor-bound protein 2 (GRB2) and Growth factor receptor-bound protein 1 (GRB1), which then activate Phosphoinositide 3-kinases (P13K) and phosphorylate Protein kinase B (AKT). Activation of P13K/AKT pathway exacerbates amyloid beta-induced inflammation and apoptosis. FGF7 has a binding site on MicroRna17 (miR-107) and overexpression of miR-107 reduces FGF7 levels.

FIGURE 2

Nerve growth factor (NGF) metabolic pathway in basal forebrain cholinergic neuron (BFCN) is mainly regulated by proteases involved in NGF maturation [tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), Plasminogen Activator Inhibitor 1 (PAI-1) and Neuroserpin)] and those involved in NGF degradation [matrix metalloproteinases (MMP9, MMP3) and tissue inhibitor of metalloproteinases 1 (TIMP-1)]. Plasmin is also responsible for proMMP-9 activation to MMP9. Extracellular signals (i.e., cytokines, hormones, and growth factor) bind to their ligands and activate Janus Kinase/signal transducer and activator of transcription (JAK/STAT). This causes dimerization of the two and allows them to be translocated to the nucleus for transcriptional response. Reactive Oxygen Species (ROS) is involved in JAK/STAT-induced Alzheimer. JAK/STAT inhibitor, folic acid and micropeptides (i.e., humorin and colivelin) attenuate JAK/STAT-induced Alzheimer. Increased astrocytes biomarker Glial fibrillary acidic protein (GFAP) and Genes were predominantly expressed on Astrocytes- STAT3-induced Alzheimer’s disease (Neurotrophic Receptor Tyrosine Kinase 3 (ntrk3), Cytochrome C Oxidase Copper Chaperone (COX17), and Grid2 Interacting Protein (Grid2ip). Decreased vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and apolipoprotein e4 (ApoE4) disrupt normal angiogenesis. Increased vascular risk factor, receptor for advanced glycation end products (RAGE) and reduced LDL-receptor related protein-1 (LRP-1) disrupt healthy tight junction. Disruption of normal angiogenesis and healthy tight junction allow Amyloid-Beta peptides efflux from vessels to brain parenchyma and promoting Amyloid-Beta plaques formation.