The newly discovered Glymphatic System: the missing link between exercise and brain health?

Dementias are responsible for the most frequent neurogenerative diseases (ND), and the seventh leading cause of death worldwide. As a result, there is a growing effort by the neuroscientific community to understand the physiopathology of ND, including how to alleviate the effects of the cognitive decline by means of non-pharmacological therapies (e.g., physical exercise). A newly discovered cleansing system in the brain, named as glymphatic system, has been linked to the pathogenesis of neurodegenerative disease. Exercise appears to improve glymphatic system function, which has significant potential implications for chronic neurological disorders such as Alzheimer's dementia (AD). Aim: To discuss recent findings concerning the possible impacts of physical exercise on the glymphatic system, with implications to the onset of ND. Literature review: One of the main hallmarks of AD is the accumulation of amyloid- peptide (A ) β β aggregates in the cerebral cortex, namely the amyloid cascade hypothesis. Impaired clearance of these substances by failure in the glymphatic system favours the accumulation of A in the cerebral parenchyma β and promote disease progression. Additionally, specialised glial cells carrying the aquaporin-4 (AQP4) water channel support the mixing of cerebrospinal fluid with interstitial fluid so to induce solute clearance. Methods: Relevant studies were identified by searching online electronic databases (i.e., Pubmed/MEDLINE and Web of Science) for peer-reviewed published articles between January 2010 and March 2023 on the glymphatic system and the possible impacts of physical exercise. Preliminary results: Considerable evidence suggests physical exercise produces a beneficial impact on the brain's health, not only reducing the pathological plaque load in individuals with Alzheimer's disease but also improving the cognitive performance of patients with mild cognitive impairment and AD. However, the way by which physical exercise modulates the glymphatic system is still unknown, as well as the effects of physical exercise on glymphatic clearance and A accumulation during aging. The literature indicates that physical exercise accelerates glymphatic β clearance and improves AQP4 expression by astrocytic cells, in a way that might attenuate A accumulation β and due neuroinflammation, protecting mice against synaptic dysfunction and decline in cognition space. Moreover, another line of research suggests prolonged exercise promotes the removal of A , attenuating its β aggregation and, later, reducing the activation of astrocytes, which favours the maintenance of the AQP4 polarity. Exercise appears to improve glymphatic system function, which has significant potential implications for chronic neurological disorders such as Alzheimer's dementia

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