Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease

Abstract

Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

Protective Effects of Polysaccharides in Neurodegenerative Diseases

“…The AD progression develops from initial short-term memory loss to behavioral problems, gradual loss of physical function, and finally death (Tarawneh and Holtzman, 2012). It is believed that the pathogenesis of AD includes the excessive aggregation of Aβ and neurofibrillary tangles formed by hyperphosphorylation of Tau protein (Zhang et al, 2021), release of pro-inflammatory cytokines (Bellucci et al, 2004), mitochondrial dysfunction (Kukreja et al, 2014), oxidative stress (Guix et al, 2012;Wahlster et al, 2013), apoptosis (Zhu et al, 2006), autophagy (Plaza-Zabala et al, 2017), and so on. The cause of AD remains unclear, and all current medications only relieve the symptoms or delay its development.…”

Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

“…Aggregated Aβ species can further convert into senile and neuritic plaques in the brain regions [ 225 ]. In addition, abnormal accumulations of Aβ can further result in the phosphorylation and aggregation of tau as NFTs [ 226 , 227 ]. These processes can cause activation of neurotoxic events that ultimately lead to cytoskeletal changes, neuronal dysfunction, and cellular death [ 227 ].…”

“…The accumulation of tau in the somatodendritic compartment can raise tau concentration in the perinuclear space and decrease the rate of nuclear import and export [ 27 ]. Pathological tau can affect the nuclear architecture by causing an abnormality in the nuclear membrane and the clumping of nuclear pores in NFT-neurons [ 160 , 161 , 227 ]. Nuclear envelope invagination caused by mutant tau leads to a toxic accumulation of mRNA [ 158 ].…”

Intratarget Microdosing for Deep Phenotyping of Multiple Drug Effects in the Live Brain

“…Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving the accumulation of amyloid-β (Aβ) plaques and tau protein-containing neurofibrillary tangles (NFTs) in conjunction with the acute and chronic inflammation leading to cognitive dysfunction (Lee et al, 2001;Spires-Jones et al, 2009;Zhang et al, 2021). While there are significant knowledge gaps around connecting molecular and cellular phenotypes observed in AD patients to clinical disease progression, specific pathophysiological features of the AD brain have been identified which have become the target of potential therapeutic interventions.…”

“…While there are significant knowledge gaps around connecting molecular and cellular phenotypes observed in AD patients to clinical disease progression, specific pathophysiological features of the AD brain have been identified which have become the target of potential therapeutic interventions. For instance, it has become evident that extracellular Aβ plaques and intraneuronal NFTs are associated with neurodegeneration and ultimately memory loss with dementia (Braak et al, 2011;Zhang et al, 2021). NFTs are intracellular aggregates of the microtubule associated protein tau, which is abnormally hyperphosphorylated by upregulation of kinase activity such as GSK-3, and CDK5 or a deficit in phosphatases such as PP2A (Spires-Jones et al, 2009;Badiola et al, 2012;Perea et al, 2020).…”