A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms
Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8397, Japan
Urology Department at Cambridge University Hospitals, NHS Foundation Trust, Addenbrooke’s Hospital, Hills Road Cambridge, Cambridge CB2 0QQ, UK
Author to whom correspondence should be addressed.
These authors contributed equally.
Received: 25 November 2020
Revised: 24 December 2020
Accepted: 31 December 2020
Published: 6 January 2021
Impairment of the immune-barrier system in the aged brain is manifested in neurodegenerative diseases, such as Alzheimer’s disease. Cerebrospinal fluid flow and drainage system of meningeal lymph scavenge the waste products in the brain parenchyma. Recent accumulating attention to the immune system in the brain is now accompanied by the expanding knowledge of the breakdown mechanism of the blood-brain barrier and increased permeability of activated immune cells at the glymphatic system, in developing brains, and in the situation of infections. These disruptions of the immune-barrier function between vasculature and brain parenchyma, where neurons locate, would also occur by infection of viruses or microorganisms, vascular injury, cerebral hemorrhage, neurological diseases, and other external factors like stress. Those activate microglia, brain-resident immune cells, and allow the infiltration of immune cells, such as macrophages, neutrophils, and T cells. Aberrant immunity disrupts the functions of neurons and prevents the maturation of glia (e.g., oligodendrocytes and astrocytes), which may cause the emergence of the highly variable psychiatric symptoms seen in schizophrenia, autism spectrum disorders, Alexander disease, and developmental disorders via an abnormality of brain activities at both cellular and organism levels. Therefore, this hypothesis challenges the longstanding neuron-centric view of neurodegenerative and psychiatric diseases.