Glial Cell-Based Vascular Mechanisms and Transplantation Therapies in Brain Vessel and Neurodegenerative Diseases

Abstract

Neurodevelopmental and neurodegenerative diseases (NDDs) with severe neurological/psychiatric symptoms, such as cerebrovascular pathology in AD, CAA, and chronic stroke, have brought greater attention with their incidence and prevalence having markedly increased over the past few years. Causes of the significant neuropathologies, especially those observed in neurological diseases in the CNS, are commonly believed to involve multiple factors such as an age, a total environment, genetics, and an immunity contributing to their progression, neuronal, and vascular injuries. We primarily focused on the studies of glial involvement/dysfunction in part with the blood-brain barrier (BBB) and the neurovascular unit (NVU) changes, and the vascular mechanisms, which have been both suggested as critical roles in chronic stroke and many other NDDs. It has been noted that glial cells including astrocytes (which outnumber other cell types in the CNS) essentially contribute more to the BBB integrity, extracellular homeostasis, neurotransmitter release, regulation of neurogenic niches in response to neuroinflammatory stimulus, and synaptic plasticity. In a recent study for NDDs utilizing cellular and molecular biology and genetic and pharmacological tools, the role of reactive astrocytes (RACs) and gliosis was demonstrated, able to trigger pathophysiological/psychopathological detrimental changes during the disease progression. We speculate, in particular, the BBB, the NVU, and changes of the astrocytes (potentially different populations from the RACs) not only interfere with neuronal development and synaptogenesis, but also generate oxidative damages, contribute to beta-amyloid clearances and disrupted vasculature, as well as lead to neuroinflammatory disorders. During the past several decades, stem cell therapy has been investigated with a research focus to target related neuro-/vascular pathologies (cell replacement and repair) and neurological/psychiatric symptoms (paracrine protection and homeostasis). Evidence shows that transplantation of neurogenic or vasculogenic cells could be achieved to pursue differentiation and maturation within the diseased brains as expected. It would be hoped that, via regulating functions of astrocytes, astrocytic involvement, and modulation of the BBB, the NVU and astrocytes should be among major targets for therapeutics against NDDs pathogenesis by drug and cell-based therapies. The non-invasive strategies in combination with stem cell transplantation such as the well-tested intranasal deliveries for drug and stem cells by our and many other groups show great translational potentials in NDDs. Neuroimaging and clinically relevant analyzing tools need to be evaluated in various NDDs brains.

EK100 and Antrodin C Improve Brain Amyloid Pathology in APP/PS1 Transgenic Mice by Promoting Microglial and Perivascular Clearance Pathways

“…Aβ clearance can be mediated by microglia. In addition, Aβ can also be cleared through vascular access [ 57 ], the glymphatic system [ 58 ], and IPAD [ 59 ]. IPAD failure can lead to cerebral amyloid angiopathy (CAA), where Aβ mainly accumulates in capillaries and arterial smooth muscle cells BM [ 4 ].…”

Nimodipine reduces delayed cerebral vasospasm after intracranial tumour surgery: A Retrospective Study

“…26 Astrocytic and neuronal vasoactive substances may also activate Ca 2+ signalling in small arteries. 27 Astrocytes mediate the neurovascular units and capillary components at the capillary level, inducing an increase in intracellular Ca 2+ in astrocytes through a purinergic receptor P2X release mechanism. 27 It has been shown that nimodipine significantly reduced symptoms caused by secondary ischaemia after SAH.…”

“…27 Astrocytes mediate the neurovascular units and capillary components at the capillary level, inducing an increase in intracellular Ca 2+ in astrocytes through a purinergic receptor P2X release mechanism. 27 It has been shown that nimodipine significantly reduced symptoms caused by secondary ischaemia after SAH. 28 Currently, nimodipine is considered as the first choice for the prevention of CVS after SAH.…”

Sex-Associated Differences in Neurovascular Dysfunction During Ischemic Stroke

“…Astrocytes serve as power reservoirs and help neurons resist ischemic injury by storing glycogen (Gurer et al, 2009) and transferring mitochondria (Hayakawa et al, 2016). Astrocytes can also secrete neurotrophic factors (Pekny et al, 2016;Zhao et al, 2021) to alleviate neuronal death. However, hypoxic astrocytes become highly swollen and cannot clear glutamate (Menyhart et al, 2021), thus aggravate neuronal excitotoxicity.…”