The Beta-Amyloid Protein of Alzheimer’s Disease: Communication Breakdown by Modifying the Neuronal Cytoskeleton

Abstract

Alzheimer's disease (AD) is one of the most prevalent severe neurological disorders afflicting our aged population. Cognitive decline, a major symptom exhibited by AD patients, is associated with neuritic dystrophy, a degenerative growth state of neurites. The molecular mechanisms governing neuritic dystrophy remain unclear. Mounting evidence indicates that the AD-causative agent, β-amyloid protein (Aβ), induces neuritic dystrophy. Indeed, neuritic dystrophy is commonly found decorating Aβ-rich amyloid plaques (APs) in the AD brain. Furthermore, disruption and degeneration of the neuronal microtubule system in neurons forming dystrophic neurites may occur as a consequence of Aβ-mediated downstream signaling. This review defines potential molecular pathways, which may be modulated subsequent to Aβ-dependent interactions with the neuronal membrane as a consequence of increasing amyloid burden in the brain.

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

“…Rho-based signaling is one of the prominent signaling cascades associated with reorganization of adhesion structures and the cytoskeleton following such stimuli (56). In neuronal cells, the ROCK pathway is involved in synaptic plasticity and activates MLCK for stimulating retraction of axonal and dendritic growth cones (93)(94)(95). Our results suggest that, similar to that on ECM proteins (72,96), cell adhesion and spreading are mediated by both ROCK and MLCK pathways (Figs.…”

Mathematical model on Alzheimer’s disease

“…The NFTs in neurons ( F i ) are formed from the hyperphosphorylated tau proteins [4, 6–9], and they are released to the extraceullar space (and are then labeled F 0 ) when the neurons die [4, 10]. Hence, …”

“…They support neuronal cross-talk, and mediate the transport of nutrients from the blood to neurons. Astrocytes are activated primarily by TNF- α , but also by A β [10, 13–16]. Activated astrocytes produce A β , but at a smaller rate than neurons [16].…”

“…ROS promotes abnormal production of A β [5, 6], which activates GSK-3 [4, 6, 8]. Activated GSK-3 mediates hyperphosphrylation of tau proteins [4, 6], which results in the formation of NFTs [10] and destruction of microtubules [4, 10], leading to neuron death. b Astrocytes are activated by [10, 16] and TNF- α [14, 15], and they produce MCP-1 [17–19], which attracts macrophages into the tissue [17, 19].…”

“…b Astrocytes are activated by [10, 16] and TNF- α [14, 15], and they produce MCP-1 [17–19], which attracts macrophages into the tissue [17, 19]. NFT activates microglias [10, 13, 15]. Activated proinflammatory microglias and microphages produce TNF- α and other proinflammatory cytokines [20, 22, 23], while anti-inflammatory microglias and macrophages produce IL-10 and other anti-inflammatory cytokines [20, 22, 23].…”