Aβ Deposition in Extracellular Space Disrupts Glial-Neuron Communication and Triggers Alzheimer's Disease

Disruptions in glial-neuron communication are linked to brain diseases; however, the exact mechanisms are not yet fully understood. This review highlights the critical role of glia-neuron interactions in sustaining normal brain functions. Under physiological conditions, astrocytes, microglia and oligodendrocytes, collaboratively regulate the homeostasis of brain structures and functions through diverse communication mechanisms. Conversely, under pathological conditions, disorders in glial-neuron communication can precipitate in neurodegenerative diseases, such as Alzheimer's Disease (AD). In AD, astrocytes use APOE to increase amyloid-beta (Aβ) deposition in the brain extracellular space (ECS) and neuron death, while microglia overactivation causes Tau overexpression and oligodendrocyte demyelination, leading to communication issues. Toxic proteins, Aβ and Tau, block brain ECS and hinder the drainage of interstitial fluid (ISF) cause the vicious cycle. The obstruction of ISF drainage certainly impedes neurotransmitter transmission, nutrient delivery, and waste removal, ultimately leading to neuronal death and cognitive decline in AD, which is also a direct factor contributing to the failure of drug delivery. Age-associated formaldehyde (FA) may act as a detrimental factor that exacerbates Aβ aggregation and promotes tau hyperphosphorylation, further aggravating ECS and ISF dysfunction. Interestingly, the interrupting the pathological cycle of FA-promoted Aβ aggregation and Aβ-induced FA generation by phototherapy and nanomedicine has been found to restore the ECS architecture and ISF drainage, which effectively improves AD symptoms. Hence, the re-establishing ECS structure and communication between neurons and glial cells may offer a promising therapeutic strategy for treating AD.