Abstract
Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer’s disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and cortices. It also led to increase in N-terminalβ-amyloid precursor protein (N-APP) and death receptor-6 (DR6) protein levels and in the activation of caspase-3 and caspase-6. Further study showed that DR6 protein was downregulated bymiR-195overexpression, upregulated bymiR-195inhibition, and unchanged by binding-site mutation and miR-masks. Knockdown of endogenousmiR-195by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) decreased the total length, numbers and crossings of dendrites and neuron death, upregulated N-APP and DR6 levels, and elevated cleaved caspase-3 and caspase-6 levels. Overexpression ofmiR-195using lenti-pre-miR-195prevented these changes triggered by 2VO. We conclude thatmiR-195is involved in CBH-induced dendritic degeneration and neuron death through activation of the N-APP/DR6/caspase pathway.
Highlights
Chronic brain hypoperfusion (CBH), which is a preclinical condition of mild cognitive impairment (MCI) and may precede Alzheimer’s disease (AD) and vascular dementia (VaD),[12,13,14] can produce neuron death,[15,16,17] whether chronic brain hypoperfusion (CBH) can induce dendritic morphological remodeling is currently unclear
Further study demonstrated that this process could be triggered by N-terminal β-amyloid precursor protein (N-APP) generated by trophic factor deprivation-induced cleavage of APP by β-site APP cleaving enzyme 1 (BACE1) because N-APP acts as a necessary and sufficient ligand for DR6.5 More importantly, recent research showed that Bcl-xL-induced impairment of neurite outgrowth was dependent on upregulation of DR6 and that DR6 expression was upregulated within dystrophic neurites in and around amyloid plaques in adult Down’s syndrome (DS) patients[19] and after hypoxia.[6]
The dendritic crossings as assessed by Sholl analysis were significantly reduced in all the hippocampal CA1 pyramidal (Figure 1m, F(1, 28) = 32, Po0.0001) and dentate gyrus (DG) granular neurons (Figure 1n, F(1, 28) = 10.41, P = 0.0032) as well as in cortical pyramidal (Figure 1o, F(1, 28) = 4.01, P = 0.049) and granular neurons (Figure 1p, F(1, 28) = 12.23, P = 0.0014) in 2VO rats compared with sham controls
Summary
Brain atrophy induced by neuronal loss is a common hallmark of Alzheimer’s disease (AD) and vascular dementia (VaD), whose other hallmarks include Aβ plaques, tau hyperphosphorylation and cholinergic neuron dysfunction.[1,2,3] Neuronal cell death, a main cause of neuronal loss, can be triggered from either the cell body (soma) or the neurites, and the two processes are controlled by different molecular events.[4,5,6,7] Importantly, impaired neurite outgrowth and Aβ toxicityinduced abnormalities in synaptic function and axonal connectivity long precede somatic cell death in hippocampal neurons,[4] suggesting that inhibition of neurite degeneration would be a potential target to prevent or treat AD and VaD. Tel/Fax: +86 451 8667-1354; Received 24.2.17; revised 16.4.17; accepted 27.4.17; Edited by G Calin miR-195 in neurites degeneration and neuron death X Chen et al as hippocampal neuronal and synaptic loss.[1,20,21,22,23,24] In a series of previous studies, we demonstrated that CBH induced by bilateral common carotid artery occlusion (2VO) impaired the learning and memory ability of rats with Aβ aggregation and tau hyperphosphorylation, which were found to be generated by upregulation of both APP and BACE1 mediated by low. Cell Death and Disease expression of microRNA-195 (miR-195).[23,24] These results led us to speculate that miR-195 may regulate dendritic morphology and neuron loss by increasing the production of N-APP, which binds with DR6 following CBH
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