Regulation of presynaptic homeostatic plasticity by glial signalling in Alzheimer's disease.

Abstract

Alzheimer's disease (AD), the most common form of dementia among the elderly, affects numerous individuals worldwide. Despite advances in understanding the molecular underpinnings of AD pathology, effective treatments to prevent or cure the disease remain elusive. AD is characterized not only by pathological hallmarks such as amyloid plaques and neurofibrillary tangles but also by impairments in synaptic physiology, circuit activity and cognitive function. Synaptic homeostatic plasticity plays a vital role in maintaining the stability of synaptic and neural functions amid genetic and environmental disturbances. A key component of this regulation is presynaptic homeostatic potentiation, where increased presynaptic neurotransmitter release compensates for reduced postsynaptic glutamate receptor functionality, thereby stabilizing neuronal excitability. The role of presynaptic homeostatic plasticity in synapse stabilization in AD, however, remains unclear. Moreover, recent advances in transcriptomics have illuminated the complex roles of glial cells in regulating synaptic function in ageing brains and in the progression of neurodegenerative diseases. Yet, the impact of AD-related abnormalities in glial signalling on synaptic homeostatic plasticity has not been fully delineated. This review discusses recent findings on how glial dysregulation in AD affects presynaptic homeostatic plasticity. There is increasing evidence that disrupted glial signalling, particularly through aberrant histone acetylation and transcriptomic changes in glia, compromises this plasticity in AD. Notably, the sphingosine signalling pathway has been identified as being protective in stabilizing synaptic physiology through epigenetic and homeostatic mechanisms, presenting potential therapeutic targets for treating neurodegenerative disorders.