Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events

Abstract

Amyloid-β (Aβ) is a dynamic peptide of Alzheimer's disease (AD) which accelerates the disease progression. At the cell membrane and cell compartments, the amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretases and engenders the Aβ. In addition, externally produced Aβ gets inside the cells by receptors mediated internalization. An elevated amount of Aβ yields spontaneous aggregation which causes organelles impairment. Aβ stimulates the hyperphosphorylation of tau protein via acceleration by several kinases. Aβ travels to the mitochondria and interacts with its functional complexes, which impairs the mitochondrial function leading to the activation of apoptotic signaling cascade. Aβ disrupts the Ca²⁺ and protein homeostasis of the endoplasmic reticulum (ER) and Golgi complex (GC) that promotes the organelle stress and inhibits its stress recovery machinery such as unfolded protein response (UPR) and ER-associated degradation (ERAD). At lysosome, Aβ precedes autophagy dysfunction upon interacting with autophagy molecules. Interestingly, Aβ act as a transcription regulator as well as inhibits telomerase activity. Both Aβ and p-tau interaction with neuronal and glial receptors elevate the inflammatory molecules and persuade inflammation. Here, we have expounded the Aβ mediated events in the cells and its cosmopolitan role on neurodegeneration, and the current clinical status of anti-amyloid therapy.

Keywords: Alzheimer’s disease; amyloid beta; gene regulation; inflammation; organelle dysfunction.

Figure 1

APP processing and Aβ generation: The PTM of APP alters Aβ production. The APP processing by the secretases (α, γ, β and η) at plasma membrane (PM), mitochondria, ER, lysosome, GC and lipid rafts generate its metabolites notably Aβ. Aβ undergoes oligomerization and plague formation at extra cellular matrix (ECM) and the ECM Aβ enters the cytoplasm through direct PM passing and receptor mediated internalization. Intra cellular Aβ accumulation in the cell organelle impairs its physiological functions.

Figure 2

Signaling of Aβ in memory impairment, tau hyperphosphorylation and cell death in AD: LRP1 receptor facilitates the Aβ clearances as well activates the FynK. Aβ binding with receptors such as mGluR, NMDAR, AMPAR, EphB2 triggers the LTD via NMDAR and AMPAR surface removal. In other hand, prolonged activation of NMDAR elevates the intracellular Ca²⁺ level which increases caspase 3. The inflammation is induced by the activation of NF-κB upon Aβ mediated activation of TLR-4, p75NTR and RAGE receptors. The tau hyperphosphorylation is induced by several kinases including GSK3β, CDK5, JNK, FynK upon Aβ binding with most of the receptors which destabilizes microtubules, forms the NFT and neurotic plaques. The LTD, NFT, inflammation, increased caspase cascade leads to dendritic spine loss and cell death.

Figure 3

Mechanism of Aβ induced mitochondrial dysfunction: Aβ enters the mitochondria (MT) through the TOM40 and TIM 23 complex. Aβ interacts with the Aβ-binding alcohol dehydrogenase (ABAD), Cyclophilin D and electron transport complexes (ETC) (C2, C3 and C5) which enhance the ROS production, Cytochrome C liberation, ROS mediated MT-DNA damage, MT impairment and mPTP opening where CytC exported to the cytoplasm. In addition, MAM bound APP fragment (C99) activates ceramides that inhibits the ETC.

Figure 4

The molecular mechanisms of Aβ prompted ER, GC and Lysosome dysfunction: Aβ induces the ER stress via increasing Ca²⁺ outflux from ER through IP₃R and RyR which accelerates the apoptosis via mitochondrial Cyt C release. The maladaptive UPR signalling in ER is facilitated via PERR, IRE1 receptors where the cells undergo apoptosis and inflammation. Aβ interacts with 20S proteosome and inhibits its functions such as degradation of the unfolded proteins. ATF6 is transported and processed in GC which acts as a transcription factor, transcribes the genes related to ERAD and XBP1. GC fragmentation is induced by the activation of several kinases which phosphorylates the GRASP65 and GM130. Autophagy and lysosome gene transcription is impeded via TFEB inhibition. On the other hand, the autophagy elongation is perturbed, as well as inhibition of autophagosome/endophagosome fusion with lysosome enhances its accumulation which drives cell death. In addition, Aβ ruptures the lysosome membrane, deacidify the niche and inhibits its hydrolases. All together the stress recovery mechanism is completely affected by the Aβ.

Figure 5

Neuroinflammation in the pathogenesis of Alzheimer’s disease: Aβ activates microglial cells via TLR and RAGE receptors which stimulates the NF-κB and AP-1 transcriptional factors leading to release of inflammatory cytokines (IL-1, IL-6, TNFα), ROS and RNS inducing oxidative/nitrosative stress mediated neuronal damage. Inflammatory cytokines stimulate astrocytes leading to amplification of inflammatory signals inducing neurotoxic effect. Chemokines also attracts peripheral immune cells towards amyloid plaque exacerbating inflammatory response.