Amyloid-beta aggregation implicates multiple pathways in Alzheimer's disease: Understanding the mechanisms

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by tau pathology and accumulations of neurofibrillary tangles (NFTs) along with amyloid-beta (Aβ). It has been associated with neuronal damage, synaptic dysfunction, and cognitive deficits. The current review explained the molecular mechanisms behind the implications of Aβ aggregation in AD via multiple events. Beta (β) and gamma (γ) secretases hydrolyzed amyloid precursor protein (APP) to produce Aβ, which then clumps together to form Aβ fibrils. The fibrils increase oxidative stress, inflammatory cascade, and caspase activation to cause hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), which ultimately lead to neuronal damage. Acetylcholine (Ach) degradation is accelerated by upstream regulation of the acetylcholinesterase (AChE) enzyme, which leads to a deficiency in neurotransmitters and cognitive impairment. There are presently no efficient or disease-modifying medications for AD. It is necessary to advance AD research to suggest novel compounds for treatment and prevention. Prospectively, it might be reasonable to conduct clinical trials with unclean medicines that have a range of effects, including anti-amyloid and anti-tau, neurotransmitter modulation, anti-neuroinflammatory, neuroprotective, and cognitive enhancement.

Keywords: Alzheimer’s disease; acetylcholine; amyloid-beta; mechanisms; neuroinflammation; oxidative stress; tau protein.

Figure 1

Beta-amyloid formation from the proteolytic digestion of the APP. AICD: APP intracellular C-terminal domain (Thinakaran and Koo, 2008).

Figure 2

Schematic diagram of AD pathology. Created with BioRender.com.

Figure 3

Diagrammatic representation of the regulatory systems for Aβ in an AD patient’s brain. Aβ, amyloid-beta; BBB, Blood–brain barrier; RAGE, Receptor for advanced glycation end products; AICD, APP intracellular C-terminal domain; APP, Amyloid precursor protein; ApoE, apolipoprotein E; E4, ApoE; E3, ApoE3; E2, ApoE2. Created with BioRender.com.

Figure 4

Metal ions’ effects on the aggregation of Aβ and tau. (A) Amyloid Plaques, (B) Tau tangle. Aβ, amyloid-beta; CDK5, Cyclin-dependent kinase; GSK-3β, Glycogen synthase kinase-3beta; NFTs, Neurofibrillary tangles; PP2A, protein phosphatase 2A (O’brien and Wong, 2011).

Figure 5

Diagram showing how Aβ and metal ions combine to cause oxidative stress in AD. Aβ, amyloid-beta; LP, Lipid peroxidation; NMDAR, N-methyl-D-aspartate receptor; VDCC, Voltage-dependent calcium channel; ER, endoplasmic reticulum; APP, Amyloid precursor protein; ATP, Adenosine triphosphate. Created with BioRender.com.

Figure 6

Diagrammatic representation of how Aβ causes neuroinflammation in AD. Aβ, amyloid-beta; NF-κB, Nuclear factor-κB; p38 MAPK, p38 Mitogen-activated protein kinases; Nrf2, Nuclear factor E2-related factor 2; IL-1β, Interleukin-1β; TNF-α, Tumor necrosis factor-α; COX-2, Cyclooxygenase-2; and iNOS, Inducible nitric oxide synthase (Schnöder et al., 2016; Lee and Kim, 2017). Created with BioRender.com.

Figure 7

Aβ and acetylcholine interactions in an AD schematic diagram. APP, Amyloid precursor protein; Aβ, Amyloid-beta; Ach, acetylcholine; AChE, acetylcholinesterase (DeTure and Dickson, 2019). Created with BioRender.com.