| Background and PurposeThe novel coronavirus(SARS-CoV-2)infects humans through the respiratory tract and causes damage and functional failure of the respiratory system and various organs of the human body.Since its first outbreak at the end of 2019,the novel coronavirus is still ravaging the world,causing great negative impact on the world economy and society.However,Angiotensin converting enzyme 2(ACE2)has attracted much attention as the typically functional receptor for the novel coronavirus.ACE2 is an important component of the renin-angiotensin system and plays an important regulatory role in the balance of RAS.Under normal physiological conditions,angiotensin Ⅱ(AngⅡ)can produce angiotensin 1-7(Ang1-7)under the catalytic action of ACE2.Next,Ang1-7,coupled with the G-protein receptor MasR,mediates various effects,including vasodilation,cardiac protection,antioxidant action,anti-inflammatory,and inhibition of Ang II-induced signaling.Therefore,the ACE2 and its by-product Angl-7 play a critical role in the treatment of cardiovascular diseases,showing a protective effect in diabetes and obesityrelated cardiomyopathy.Previous studies have shown that ACE2 expression is downregulated in patients infected with SARS-CoV-2,which promotes the lung inflammatory process and subsequent factor storm,leading to multiple organ failure.Follow-up clinical data showed that as a respiratory system-related disease,patients with COVID-19 would not only show respiratory system-related symptoms,but also some central nervous systemrelated symptoms,such as depression,headache and "brain fog"(symptoms such as confusion and forgetfulness).Moreover,SARS-CoV-2 has also been detected by taking cerebrospinal fluid from COVID-19 patients or conducting autopsies on postmortem samples of their brains.These data suggest that SARS-CoV-2 can bind to ACE2 and invade the central nervous system as well as attack brain cells directly.However,the anatomical distribution of ACE2 receptors in various brain regions of the human brain remains unclear.In addition,Alzheimer’s disease(AD),a complication of COVID-19 in the central nervous system,has also become a growing concern.AD is a neurodegenerative disease commonly found in the elderly.Patients often accompanied with cognitive dysfunction and abnormal mental behavior.AD patients have a high risk of viral infection and tissue damage due to the destruction of the blood-brain barrier and the dysregulation of the brain immune system.In addition,the management of AD is not compatible with the management of COVID-19 isolation,resulting in the additional burden of COVID-19 on the treatment and care of AD.Likewise,it is not clear whether the anatomic distribution of ACE2 changes in various brain regions in AD patients.Therefore,this study clarified the anatomical distribution of ACE2 in 12 brain regions of human brain,providing a theoretical basis for people to understand and deal with CNS related symptoms of COVID-19.Moreover,the changes in the anatomical distribution of ACE2 in various brain regions of AD patients were further explored,providing clues for the subsequent study of the pathological relationship between COVID-19 and AD.Materials and MethodsMaterialsThe paraffin section samples of 12 brain regions of 5 neurologically healthy subjects and 5 AD patients used in this study were obtained from the National Developmental and Functional Human Brain Bank.In addition,considering the interference caused by gender difference to the experimental results,the 10 samples used in this study were all female.Twelve of the brain regions were superior temporal gyrus;inferior apical leaflets;midbrain;pons;cerebellar cortex and dentate nucleus;medulla;basal ganglia;hippocampus and entorhinal cortex;middle frontal gyrus;visual cortex;amygdala and anterior cingulate gyrus.Methods1.Basic information collection and assessment of prenatal cognitive status of donors in the National Developmental and Functional Human Brain Tissue Bank:Demographic information and prenatal medical history of brain donors are collected through ethically approved body donation procedures,and the prenatal cognitive status of donors is assessed using the ECOG questionnaire provided by knowledgeable individuals.2.Neuropathological evaluation of donated samples from the National Developmental and Functional Human Brain Tissue Bank:detection of Aβ plaques using Aβ antibodies;Detection of neurofibrillary tangles by p-Tau antibody;The modified Bielschowsky silver staining method was used to detect neuroinflammatory plaques,and AD neuropathological scores were performed for each relevant brain region according to the internationally accepted "ABC" scoring system(NIA-AA guidelines).3.The anatomical distribution characteristics of ACE2 in 12 brain regions in neurologically healthy human subjects were evaluated by the immunohistochemical staining and the changes of the anatomical distribution in different brain regions of AD patients was explored.4.Immunofluorescence staining was used to identify the types of cells expressing ACE2 in human brain and the variation of expression in different brain regions in neurologically healthy subjects and AD patients.Results1.The expression of ACE2 in the 12 brain regions of healthy subjects:(1)ACE2 positive signals were mainly found in endothelial cells and non-vascular cells.(2)In neurologically healthy individuals,ACE2 expression is relatively high in the pons,optic cortex and amygdala,but relatively low in the midbrain,cerebellum,dentate nucleus and medulla.2.The changes in the anatomical distribution of ACE2 in patients with AD:(1)The relative expression levels of ACE2 was significantly reduced in the hippocampus;basal ganglia;middle frontal gyrus;entorhinal cortex;visual cortex;amygdala and amygdala of AD patients.(2)Excluded the positive ACE2 signal of endothelial cells,the positive ACE2 signal of non-vascular cells was significantly reduced in the middle frontal gyrus,visual cortex and basal ganglia of AD patients.3.The cell types of mainly expressed ACE2 in the brain regions:(1)ACE2 is mainly expressed in neurons of the brain,with a small amount of ACE2 expressed in astrocytes and microglia.In addition,the expression of ACE2 on the neurons of AD patients was significantly decreased,but there remained significantly unchanged in astrocytes and microglia.Conclusions1.In neurologically healthy human individuals,ACE2 expression is relatively high in the pons,optic cortex,and amygdala but relatively low in the midbrain,cerebellum,dentate nucleus,and medulla.2.The expression of ACE2 was decreased significantly in the basal ganglia,visual cortex and middle frontal gyrus of AD patients.3.ACE2 is mainly expressed in neurons in the brain and is significantly decreased in the neurons of AD patients.Clinical significanceIn this study,the anatomical distribution map of ACE2 in 12 brain regions of Chinese human brain was drawn for the first time,providing a theoretical basis for people to understand and deal with the central nervous system symptoms of COVID-19 patients.Furthermore,the changes in the anatomical distribution of ACE2 in AD pathology were also revealed,providing clues for the subsequent study of the pathological relationship between COVID-19 and AD. |
PDF Full Text Request