Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Progress and challenges of cerebrovascular endothelial cells research promoted by single-cell transcriptome sequencing technology

Single-cell transcriptome sequencing has been a rapidly developing and powerful biological tool in recent years,and it plays a vital role in describing tissue development,cell heterogeneity,stress response,etc.Cerebrovascular disease is one of the leading causes affecting human health in the world.Thus,it is important to understand the characteristics of cerebrovascular structure,function,and environmental response.Notably,single-cell transcriptome sequencing provides deeper insights into cerebrovascular research in health and disease states.This article will briefly introduce the basic structure and function of cerebrovascular endothelial cells(ECs),summarize the current research and new findings on cerebrovascular ECs at the single-cell transcriptome level,and discuss the challenges in this field.

Dysfunction of blood-brain barrier in cerebral amyloid angiopathy

Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substances,which is closely related to neurodegenerative diseases.In CAA,the deposition of amyloid beta(Aβ)in arteries,capillaries,and arterioles of meninges and cerebral cortex results in the destruction of the BBB,chronic inflammatory response,chronic cerebral hypoperfusion,and dysfunction of the neurovascular unit,which eventually leads to neurodegeneration.At the same time,CAA is an age-related disease.Patients with CAA often have some risk factors for cerebrovascular diseases,such as hypertension and diabetes,which can further aggravate the damage to the BBB.Thus,it is of great significance to pay attention to the BBB in the pathogenesis and future intervention targets of CAA.Therefore,this manuscript reviewed the dysfunction of the BBB in CAA.