The duality of amyloid-β: its role in normal and Alzheimer's disease states

Abstract

Alzheimer's disease (AD) is a degenerative neurological condition that gradually impairs cognitive abilities, disrupts memory retention, and impedes daily functioning by impacting the cells of the brain. A key characteristic of AD is the accumulation of amyloid-beta (Aβ) plaques, which play pivotal roles in disease progression. These plaques initiate a cascade of events including neuroinflammation, synaptic dysfunction, tau pathology, oxidative stress, impaired protein clearance, mitochondrial dysfunction, and disrupted calcium homeostasis. Aβ accumulation is also closely associated with other hallmark features of AD, underscoring its significance. Aβ is generated through cleavage of the amyloid precursor protein (APP) and plays a dual role depending on its processing pathway. The non-amyloidogenic pathway reduces Aβ production and has neuroprotective and anti-inflammatory effects, whereas the amyloidogenic pathway leads to the production of Aβ peptides, including Aβ40 and Aβ42, which contribute to neurodegeneration and toxic effects in AD. Understanding the multifaceted role of Aβ, particularly in AD, is crucial for developing effective therapeutic strategies that target Aβ metabolism, aggregation, and clearance with the aim of mitigating the detrimental consequences of the disease. This review aims to explore the mechanisms and functions of Aβ under normal and abnormal conditions, particularly in AD, by examining both its beneficial and detrimental effects.

Keywords: Alzheimer’s disease; Beta amyloid; Cognitive decline; Long-term potentiation; Neuroinflammation; Neuroprotection; Neurotoxicity.

Fig. 1

The non-amyloidogenic pathway plays a role in prevents the generation of Aβ by cleaving APP at α-secretase. In contrast, the amyloidogenic pathway involves β-secretase and γ-secretase, which are responsible for APP processing and contribute to the production of Aβ. Maintaining a balance between these pathways is important for the regulation of Aβ generation and its potential role in AD

Fig. 2

Two pathways delineate the fate of APP: the physiological route, where alpha-secretase cleaves APP to yield neuroprotective sAPPα and the benign C83 fragment, promoting neuronal health; and the pathophysiological cascade involving β-secretase and γ-secretase, producing toxic C99 (β-CTF) and subsequent Aβ peptides, notably Aβ42, leading to oligomerization, plaque formation, synaptic dysfunction, and neuronal damage. The former pathway emphasizes beneficial effects on neuronal function and signaling, whereas the latter links Aβ aggregates to neurotoxicity, oxidative stress, and inflammation, hallmarking AD progression

Fig. 3

Aβ oligomers have a detrimental impact on various receptors in the brain, including Frizzled receptors, PrPc, NMDA receptors, insulin receptors, and NGF receptors. Their interaction with these receptors leads to tau phosphorylation, activation of GSK-3β, synaptic dysfunction, excitotoxicity, disruption of insulin signaling, impairment of NGF signaling, and ultimately, cell death. These complex interactions contribute to the progression of AD and underscore the importance of understanding and targeting Aβ oligomers to develop effective therapeutic strategies

Fig. 4

Aβ plays a role in triggering the activation of NF-κB, a central regulator of inflammation, through various pathways in neurons and microglia cells, contributing to the development of AD. In microglia cells, one pathway by which Aβ induces NF-κB activation is the Toll-like receptor (TLR) pathway. Aβ interacts with TLR2 and TLR4, leading to the recruitment of adaptor proteins like MyD88. This activates downstream signaling molecules, including interleukin-1 receptor-associated kinases (IRAKs). The phosphorylation of IRAKs leads to the activation of the transforming growth factor-beta-activated kinase 1 (TAK1) complex. The TAK1 complex, along with the inhibitor of κB kinase (IKK) complex, phosphorylates and degrades IκB, releasing NF-κB from its inhibitory state. NF-κB then translocates into the nucleus, where it forms a transcriptional complex with coactivators and binds to κB sites in the promoters of proinflammatory genes such as IL-1β and TNF-α, promoting their expression. In neurons, Aβ can activate NF-κB through the T-cell receptor (TCR) pathway. Aβ peptides interact with major histocompatibility complex class II (MHC-II) molecules on antigen-presenting cells like microglia. This triggers TCR signaling in T cells, leading to the release of proinflammatory cytokines, including IFN-γ. IFN-γ binds to its receptors on neurons, initiating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling. The JAK-STAT pathway activates transcription factors, including STAT1 and STAT3, which collaborate with NF-κB to enhance its activity. This collaboration promotes the expression of proinflammatory genes. Furthermore, Aβ can activate NF-κB through the tumor necrosis factor receptor (TNFR) pathway in both neurons and microglia cells. By interacting with TNFR, Aβ triggers the recruitment and activation of TNFR-associated factor (TRAF) proteins, particularly TRAF2 and TRAF6. These proteins activate the IKK complex, which includes IKKα, IKKβ, and IKKγ. The activated IKK complex phosphorylates IκB, leading to its ubiquitination and degradation. The degradation of IκB releases NF-κB, allowing its translocation into the nucleus. In the nucleus, NF-κB forms a transcriptional complex that promotes the transcription of proinflammatory genes. Overall, these pathways highlight how Aβ can initiate NF-κB activation in both microglia cells and neurons, leading to the expression of proinflammatory genes and contributing to the inflammatory processes observed in AD [252, 253]