Membrane interaction to intercellular spread of pathology in Alzheimer’s disease

Abstract

Progressive development of pathology is one of the major characteristic features of neurodegenerative diseases. Alzheimer’s disease (AD) is the most prevalent among them. Extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles are the pathological phenotypes of AD. However, cellular and animal studies implicate tau as a secondary pathology in developing AD while Aβ aggregates is considered as a trigger point. Interaction of Aβ peptides with plasma membrane (PM) seems to be a promising site of involvement in the events that lead to AD. Aβ binding to the lipid membranes initiates formation of oligomers of Aβ species, and these oligomers are known as primary toxic agents for neuronal toxicities. Once initiated, neuropathological toxicities spread in a “prion-like” fashion probably through the mechanism of intercellular transfer of pathogenic aggregates. In the last two decades, several studies have demonstrated neuron-to-neuron transfer of neurodegenerative proteins including Aβ and tau via exosomes and tunneling nanotubes (TNTs), the two modes of long-range intercellular transfer. Emerging pieces of evidence indicate that molecular pathways related to the biogenesis of exosomes and TNTs interface with endo-lysosomal pathways and cellular signaling in connection to vesicle recycling-imposed PM and actin remodulation. In this review, we discuss interactions of Aβ aggregates at the membrane level and its implications in intercellular spread of pathogenic aggregates. Furthermore, we hypothesize how spread of pathogenic aggregates contributes to complex molecular events that could regulate pathological and synaptic changes related to AD.

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

“…Consistent with the strong genetic evidence that supports the involvement of abnormal lipids in AD pathogenesis (Fig. 1), membrane lipid composition and integrity along with neuroinflammation and oxidative stress have been suggested to play an important role in AD pathogenesis [59][60][61]. Decreased phospholipids (PC, PE, and PI) have been reported in AD cohorts (reviewed in [62]).…”

Exosomes in brain diseases: Pathogenesis and therapeutic targets

“…The accumulation of Aβ 1-42 in the brain and the phosphorylation of tau protein are the two main pathological features of AD. 171 Exosomes are involved in neuroinflammation, 172 productions and clearance of Aβ, 173,174 transport of Aβ, tau, prions, and α-synaptic nucleoproteins, 175,176 which trigger the hyperphosphorylation of Aβ and tau. 177 Intracranial injection of exosomes from AD mouse brains in wild-type (WT) mice resulted in mitochondrial damage and neurotoxicity.…”

Aβ40 Aggregation under Changeable Conditions

“…Here, we evaluated the effect of changes in the electrostatic repulsion on Aβ40 aggregation, taking into consideration the different environments that this peptide can encounter in the cell [1,6,22,[37][38][39]48,49]. We also presumed that the conditions in the cell can change and that different Aβ40 assemblies can rise and interact.…”