Consistent immunohistochemical detection of intracellular β-amyloid42 in pyramidal neurons of Alzheimer's disease entorhinal cortex

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.

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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.

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Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex

Brain Pathology ◽

10.1111/bpa.13005 ◽

2021 ◽

Author(s):

Jason H. Y. Yeung ◽

Joshua L. Walby ◽

Thulani H. Palpagama ◽

Clinton Turner ◽

Henry J. Waldvogel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Receptor Expression

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Reelin-immunoreactive Cajal-Retzius cells: the entorhinal cortex in normal aging and Alzheimer's disease

Acta Neuropathologica ◽

10.1007/s00401-003-0729-7 ◽

2003 ◽

Vol 106 (4) ◽

pp. 291-302 ◽

Cited By ~ 17

Author(s):

Anett Riedel ◽

Riitta Miettinen ◽

Jens Stieler ◽

Mia Mikkonen ◽

Irina Alafuzoff ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Normal Aging ◽

Retzius Cells

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Loss of stimulatory effect of guanosine triphosphate on [35S]GTPγS binding correlates with Alzheimer's disease neurofibrillary pathology in entorhinal cortex and CA1 hippocampal subfield

Journal of Neuroscience Research ◽

10.1002/jnr.10125 ◽

2001 ◽

Vol 67 (3) ◽

pp. 388-398 ◽

Cited By ~ 14

Author(s):

A. García-Jiménez ◽

R.F. Cowburn ◽

T.G. Ohm ◽

H. Lasn ◽

B. Winblad ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Neurofibrillary Pathology ◽

Guanosine Triphosphate ◽

Gtpγs Binding

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Stereologic analysis of hippocampal Alzheimer's disease pathology in the oldest-old: Evidence for sparing of the entorhinal cortex and CA1 field

Experimental Neurology ◽

10.1016/j.expneurol.2004.12.005 ◽

2005 ◽

Vol 193 (1) ◽

pp. 198-206 ◽

Cited By ~ 36

Author(s):

Armin von Gunten ◽

Enikö Kövari ◽

Claire-Bénédicte Rivara ◽

Constantin Bouras ◽

Patrick R. Hof ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Oldest Old ◽

Stereologic Analysis ◽

Old Evidence

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Alzheimer’s Disease: From Amyloid to Autoimmune Hypothesis

The Neuroscientist ◽

10.1177/1073858420908189 ◽

2020 ◽

Vol 26 (5-6) ◽

pp. 455-470

Author(s):

Yuri I. Arshavsky

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Pyramidal Neurons ◽

Adaptive Immune System ◽

Memory Formation ◽

Autoimmune Response ◽

Prevention And Treatment ◽

Ad Prevention ◽

Clinical Verification

Although Alzheimer’s disease (AD) was described over a century ago, there are no effective approaches to its prevention and treatment. Such a slow progress is explained, at least in part, by our incomplete understanding of the mechanisms underlying the pathogenesis of AD. Here, I champion a hypothesis whereby AD is initiated on a disruption of the blood-brain barrier (BBB) caused by either genetic or non-genetic risk factors. The BBB disruption leads to an autoimmune response against pyramidal neurons located in the allo- and neocortical structures involved in memory formation and storage. The response caused by the adaptive immune system is not strong enough to directly kill neurons but may be sufficient to make them selectively vulnerable to neurofibrillary pathology. This hypothesis is based on the recent data showing that memory formation is associated with epigenetic chromatin modifications and, therefore, may be accompanied by expression of memory-specific proteins recognized by the immune system as “non-self” antigens. The autoimmune hypothesis is testable, and I discuss potential ways for its experimental and clinical verification. If confirmed, this hypothesis can radically change therapeutic approaches to AD prevention and treatment.

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