3D analysis of the synaptic organization in the Entorhinal cortex in Alzheimer’s disease

AbstractThe entorhinal cortex (EC) is especially vulnerable in the early stages of Alzheimer’s disease (AD). In particular, cognitive deficits have been linked to alterations in the upper layers of EC. In the present report, we performed light microscopy analysis and 3D ultrastructural analyses of synapses in the EC using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to examine possible alterations related to AD. We analyzed 5000 synaptic junctions that were 3D reconstructed, representing the largest 3D ultrastructural study of synapses in the EC of the human brain from cases with AD performed to date. Structural differences were found in the AD tissue at the light microscope level and at the ultrastructural level. These differences may play a role in the anatomical basis for the impairment of cognitive functions in AD.

Download Full-text

3D analysis of the synaptic organization in the Entorhinal cortex in Alzheimer’s disease

eNeuro ◽

10.1523/eneuro.0504-20.2021 ◽

2021 ◽

pp. ENEURO.0504-20.2021

Author(s):

M Domínguez-Álvaro ◽

M Montero-Crespo ◽

L Blazquez-Llorca ◽

S Plaza-Alonso ◽

N Cano-Astorga ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

3D Analysis ◽

Synaptic Organization

Download Full-text

3D Ultrastructural Study of Synapses in the Human Entorhinal Cortex

Cerebral Cortex ◽

10.1093/cercor/bhaa233 ◽

2020 ◽

Vol 31 (1) ◽

pp. 410-425 ◽

Cited By ~ 1

Author(s):

M Domínguez-Álvaro ◽

M Montero-Crespo ◽

L Blazquez-Llorca ◽

J DeFelipe ◽

L Alonso-Nanclares

Keyword(s):

Entorhinal Cortex ◽

Focused Ion Beam ◽

Functional Organization ◽

Structural Parameters ◽

Ion Beam ◽

Three Dimensional ◽

Ultrastructural Level ◽

3D Analysis ◽

Synaptic Organization ◽

Health And Disease

Abstract The entorhinal cortex (EC) is a brain region that has been shown to be essential for memory functions and spatial navigation. However, detailed three-dimensional (3D) synaptic morphology analysis and identification of postsynaptic targets at the ultrastructural level have not been performed before in the human EC. In the present study, we used Focused Ion Beam/Scanning Electron Microscopy to perform a 3D analysis of the synapses in the neuropil of medial EC in layers II and III from human brain autopsies. Specifically, we studied synaptic structural parameters of 3561 synapses, which were fully reconstructed in 3D. We analyzed the synaptic density, 3D spatial distribution, and type (excitatory and inhibitory), as well as the shape and size of each synaptic junction. Moreover, the postsynaptic targets of synapses could be clearly determined. The present work constitutes a detailed description of the synaptic organization of the human EC, which is a necessary step to better understand the functional organization of this region in both health and disease.

Download Full-text

Ultrastructral Analysis of Synapse in a Drosophila of the Swedish Mutation which Causes Early-Onset Alzheimer's Disease using Focused Ion Beam Microscopy

Microscopy and Microanalysis ◽

10.1017/s1431927611001954 ◽

2011 ◽

Vol 17 (S2) ◽

pp. 216-217

Author(s):

S Park ◽

A Schertel ◽

S Han

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Focused Ion Beam ◽

Ion Beam ◽

Swedish Mutation ◽

Early Onset Alzheimer’S Disease

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011.

Download Full-text

P1-178: Early astrocytic atrophy in the Entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.728 ◽

2010 ◽

Vol 6 ◽

pp. S225-S225

Author(s):

Chia-Yu Yeh ◽

Markel Olabarria ◽

Harun N. Noristani ◽

Alexei Verkhratsky ◽

Jose J. Rodriguez

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Entorhinal Cortex ◽

Transgenic Animal ◽

Transgenic Animal Model ◽

Model Of Alzheimer’S Disease

Download Full-text

Protective effect of APOE epsilon 2 on intrinsic functional connectivity of the entorhinal cortex is associated with better episodic memory in elderly individuals with risk factors for Alzheimer's disease

Oncotarget ◽

10.18632/oncotarget.11289 ◽

2016 ◽

Vol 7 (37) ◽

pp. 58789-58801 ◽

Cited By ~ 8

Author(s):

Jiu Chen ◽

Hao Shu ◽

Zan Wang ◽

Duan Liu ◽

Yongmei Shi ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Connectivity ◽

Episodic Memory ◽

Protective Effect ◽

Entorhinal Cortex ◽

Elderly Individuals ◽

Intrinsic Functional Connectivity

Download Full-text

Bioinformatics analysis of differentially expressed genes and identification of an miRNA–mRNA network associated with entorhinal cortex and hippocampus in Alzheimer’s disease

Hereditas ◽

10.1186/s41065-021-00190-0 ◽

2021 ◽

Vol 158 (1) ◽

Author(s):

Haoming Li ◽

Linqing Zou ◽

Jinhong Shi ◽

Xiao Han

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differentially Expressed Genes ◽

Entorhinal Cortex ◽

Molecular Mechanisms ◽

Kegg Pathway ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Differentially Expressed ◽

Hub Genes

Abstract Background Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, and the lesions originate in the entorhinal cortex (EC) and hippocampus (HIP) at the early stage of AD progression. Gaining insight into the molecular mechanisms underlying AD is critical for the diagnosis and treatment of this disorder. Recent discoveries have uncovered the essential roles of microRNAs (miRNAs) in aging and have identified the potential of miRNAs serving as biomarkers in AD diagnosis. Methods We sought to apply bioinformatics tools to investigate microarray profiles and characterize differentially expressed genes (DEGs) in both EC and HIP and identify specific candidate genes and pathways that might be implicated in AD for further analysis. Furthermore, we considered that DEGs might be dysregulated by miRNAs. Therefore, we investigated patients with AD and healthy controls by studying the gene profiling of their brain and blood samples to identify AD-related DEGs, differentially expressed miRNAs (DEmiRNAs), along with gene ontology (GO) analysis, KEGG pathway analysis, and construction of an AD-specific miRNA–mRNA interaction network. Results Our analysis identified 10 key hub genes in the EC and HIP of patients with AD, and these hub genes were focused on energy metabolism, suggesting that metabolic dyshomeostasis contributed to the progression of the early AD pathology. Moreover, after the construction of an miRNA–mRNA network, we identified 9 blood-related DEmiRNAs, which regulated 10 target genes in the KEGG pathway. Conclusions Our findings indicated these DEmiRNAs having the potential to act as diagnostic biomarkers at an early stage of AD.

Download Full-text

EAAT2 Expression in the Hippocampus, Subiculum, Entorhinal Cortex and Superior Temporal Gyrus in Alzheimer’s Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.702824 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jason H. Y. Yeung ◽

Thulani H. Palpagama ◽

Oliver W. G. Wood ◽

Clinton Turner ◽

Henry J. Waldvogel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Expression Patterns ◽

Superior Temporal Gyrus ◽

Altered Expression ◽

And Control ◽

Transporter Expression

Alzheimer’s disease (AD) is a neuropathological disorder characterized by the presence and accumulation of amyloid-beta plaques and neurofibrillary tangles. Glutamate dysregulation and the concept of glutamatergic excitotoxicity have been frequently described in the pathogenesis of a variety of neurodegenerative disorders and are postulated to play a major role in the progression of AD. In particular, alterations in homeostatic mechanisms, such as glutamate uptake, have been implicated in AD. An association with excitatory amino acid transporter 2 (EAAT2), the main glutamate uptake transporter, dysfunction has also been described. Several animal and few human studies examined EAAT2 expression in multiple brain regions in AD but studies of the hippocampus, the most severely affected brain region, are scarce. Therefore, this study aims to assess alterations in the expression of EAAT2 qualitatively and quantitatively through DAB immunohistochemistry (IHC) and immunofluorescence within the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus (STG) regions, between human AD and control cases. Although no significant EAAT2 density changes were observed between control and AD cases, there appeared to be increased transporter expression most likely localized to fine astrocytic branches in the neuropil as seen on both DAB IHC and immunofluorescence. Therefore, individual astrocytes are not outlined by EAAT2 staining and are not easily recognizable in the CA1–3 and dentate gyrus regions of AD cases, but the altered expression patterns observed between AD and control hippocampal cases could indicate alterations in glutamate recycling and potentially disturbed glutamatergic homeostasis. In conclusion, no significant EAAT2 density changes were found between control and AD cases, but the observed spatial differences in transporter expression and their functional significance will have to be further explored.

Download Full-text

Cognitive Improvement is Correlated with Increased Dynamic Functional Connectivity of Default Mode Network by Personalized rTMS in Alzheimer's Disease

10.21203/rs.3.rs-554187/v1 ◽

2021 ◽

Author(s):

Lili Wei ◽

Jintao Wang ◽

Yingchun Zhang ◽

Luoyi Xu ◽

Kehua Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Connectivity ◽

Default Mode Network ◽

Present Report ◽

Verbal Learning ◽

Dynamic Functional Connectivity ◽

Default Mode ◽

Cognitive Improvement ◽

Promising Therapeutic Approach

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) is thought to be a promising therapeutic approach for Alzheimer's disease patients. Methods In the present report, a double-blind, randomized, sham-controlled rTMS trial was conducted in mild-to-moderate Alzheimer's disease patients. High-frequency rTMS was delivered to a subject-specific left lateral parietal region that demonstrated highest functional connectivity with the hippocampus using resting-state fMRI. The Mini Mental State Examination (MMSE) and Philadelphia Verbal Learning Test (PVLT) were used to evaluate patients’ cognitive functions. Results Patients receiving active rTMS treatment (n = 31) showed a significant increase in the MMSE, PVLT-Immediate recall, and PVLT-Short Delay recall scores after two weeks of rTMS treatment, whereas patients who received sham rTMS (n = 27) did not show significant changes in these measures. Dynamic functional connectivity (dFC) magnitude of the default mode network (DMN) in the active-rTMS group showed a significant increase after two weeks of rTMS treatment, and no significant changes were found in the sham-rTMS group. There was a significantly positive correlation between changes of the MMSE and changes of the dFC magnitude of DMN in the active-rTMS group, but not the sham-rTMS group. Conclusions Our findings are novel in demonstrating the feasibility and effectiveness of the fMRI-guided rTMS treatment in Alzheimer's disease patients, and DMN might play a vital role in therapeutic effectiveness of rTMS in Alzheimer’s disease. Trial registration: China National Medical Research Platform (http://114.255.48.20/login, No:MR-33-20-004217), retrospectively registered 2020-12-23.

Download Full-text