Neurochemical Dissection of Synaptic Pathology in Alzheimer's Disease

1998 ◽  
Vol 10 (1) ◽  
pp. 11-23 ◽  
Author(s):  
Pia Davidsson ◽  
Kaj Blennow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Cortex ◽  
Late Onset ◽  
Synaptic Proteins ◽  
Presynaptic Membrane ◽  
Control Value ◽  
Postsynaptic Protein ◽  
Post Mortem Brain ◽  
Synaptic Pathology

Synaptic pathology has attained increasing attention as being central in the pathogenesis of Alzheimer's disease (AD). To address the question whether synaptic pathology in AD involves the whole synapse, or is limited to specific components thereof, we studied three different synaptic vesicle proteins (rab3a, synaptotagmin, synaptophysin) and also the presynaptic membrane protein GAP-43 and the postsynaptic protein neurogranin. The material included post-mortem brain tissue (frontal cortex, hippocampus, and cerebellum) from 8 patients with early-onset AD (EAD), 11 patients with late-onset AD (LAD), 6 patients with vascular dementia (VAD), and 9 control subjects. A reduction of all synaptic proteins was found in AD, more pronounced in EAD than in LAD, in both the frontal cortex (EAD 30% to 70% vs. LAD 82% to 88% of control value) and hippocampus (EAD 22% to 82% vs. LAD 76% to 89% of control value), whereas only minor changes were found in VAD. The finding that all synaptic proteins were reduced in AD suggests a degeneration and loss of whole synaptic elements that are more pronounced in EAD than in LAD.

P4-019: Postsynaptic protein PSD-95 expression is correlated to clinical indexes in the anterior cingulate and frontal cortex of Alzheimer's disease cases

2011 ◽  
Vol 7 ◽  
pp. S704-S704
Author(s):  
Geneviève Leuba ◽  
Timothy Volonakis ◽  
Natalia Fernandez ◽  
Sabine Joray ◽  
André Vernay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Cortex ◽  
Anterior Cingulate ◽  
Postsynaptic Protein

scholarly journals Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

2020 ◽  
Author(s):  
Vaishnavi S. Jadhav ◽  
Peter BC. Lin ◽  
Guixiang Xu ◽  
Taylor Pennington ◽  
Gonzalo Viana Di Prisco ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Late Onset ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Presenile Dementia ◽  
Altered Expression ◽  
Protein Levels

Abstract Background:Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and NasuHakola Disease (NHD). The Trem2 variantR47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linkedTrem2 variants like Y38Care associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2species predispose individuals to presenile dementia.Methods:To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function, we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38/Y38C and Trem2-/-mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results:While mice harboring Trem2 Y38C exhibited normal expression levels of Trem2, the pathological outcomes phenocopied Trem2-/- miceat 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion:Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38Cand Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like tau or amyloid. This suggests TREM2 impacts neuronal functions and providesmolecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

scholarly journals Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Vaishnavi S. Jadhav ◽  
Peter B. C. Lin ◽  
Taylor Pennington ◽  
Gonzalo Viana Di Prisco ◽  
Asha Jacob Jannu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Late Onset ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Presenile Dementia ◽  
Altered Expression ◽  
Protein Levels

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

scholarly journals Genome-Wide DNA Methylation Differences Between Late-Onset Alzheimer's Disease and Cognitively Normal Controls in Human Frontal Cortex

2012 ◽  
Vol 29 (3) ◽  
pp. 571-588 ◽  
Author(s):  
Kelly M. Bakulski ◽  
Dana C. Dolinoy ◽  
Maureen A. Sartor ◽  
Henry L. Paulson ◽  
John R. Konen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Frontal Cortex ◽  
Late Onset ◽  
Cognitively Normal ◽  
Genome Wide ◽  
Human Frontal Cortex ◽  
Normal Controls

scholarly journals Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

2020 ◽  
Author(s):  
Vaishnavi S. Jadhav ◽  
Peter BC. Lin ◽  
Taylor Pennington ◽  
Gonzalo Viana Di Prisco ◽  
Asha Jacob Jannu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Late Onset ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Presenile Dementia ◽  
Altered Expression ◽  
Protein Levels

Abstract Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia.Methods: To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2-/- mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results: While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2-/- mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion: Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

scholarly journals Ethnicity-specific and overlapping alterations of brain hydroxymethylome in Alzheimer’s disease

2019 ◽  
Vol 29 (1) ◽  
pp. 149-158
Author(s):  
Lixia Qin ◽  
Qian Xu ◽  
Ziyi Li ◽  
Li Chen ◽  
Yujing Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Cortex ◽  
Cytosine Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Hypoxia Inducible Factor ◽  
Specific Gene ◽  
Dna Hydroxymethylation ◽  
Genome Wide

Abstract 5-Methylcytosine (5mC), generated through the covalent addition of a methyl group to the fifth carbon of cytosine, is the most prevalent DNA modification in humans and functions as a critical player in the regulation of tissue and cell-specific gene expression. 5mC can be oxidized to 5-hydroxymethylcytosine (5hmC) by ten–eleven translocation (TET) enzymes, which is enriched in brain. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and several studies using the samples collected from Caucasian cohorts have found that epigenetics, particularly cytosine methylation, could play a role in the etiological process of AD. However, little research has been conducted using the samples of other ethnic groups. Here we generated genome-wide profiles of both 5mC and 5hmC in human frontal cortex tissues from late-onset Chinese AD patients and cognitively normal controls. We identified both Chinese-specific and overlapping differentially hydroxymethylated regions (DhMRs) with Caucasian cohorts. Pathway analyses revealed specific pathways enriched among Chinese-specific DhMRs, as well as the shared DhMRs with Caucasian cohorts. Furthermore, two important transcription factor-binding motifs, hypoxia-inducible factor 2α (HIF2α) and hypoxia-inducible factor 1α (HIF1α), were enriched in the DhMRs. Our analyses provide the first genome-wide profiling of DNA hydroxymethylation of the frontal cortex of AD patients from China, emphasizing an important role of 5hmC in AD pathogenesis and highlighting both ethnicity-specific and overlapping changes of brain hydroxymethylome in AD.

Familial Patterns of Risk in Very Late-Onset Alzheimer's Disease

2003 ◽  
Author(s):  
J. M. Silverman ◽  
C. J. Smith ◽  
D. B. Marin ◽  
R. C. Mohs ◽  
C. B. Propper
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Familial Patterns

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Sharifa Hasana ◽  
Md. Farhad Hossain ◽  
Md. Siddiqul Islam ◽  
Tapan Behl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Massively Parallel Sequencing ◽  
Late Onset ◽  
Current Knowledge ◽  
The Elderly ◽  
Apoe Ε4 ◽  
Sequencing Technologies ◽  
Genetic Components ◽  
Ε4 Allele

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

Alzheimer’s Disease and Retinal Degeneration: A Glimpse at Essential Trace Metals in Ocular Fluids and Tissues

2020 ◽  
Vol 16 (12) ◽  
pp. 1073-1083 ◽  
Author(s):  
Alessandra Micera ◽  
Luca Bruno ◽  
Andrea Cacciamani ◽  
Mauro Rongioletti ◽  
Rosanna Squitti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Trace Metals ◽  
Late Onset ◽  
Current Knowledge ◽  
Pathological Condition ◽  
Retinal Disease ◽  
Cellular Aging ◽  
Research Strategies ◽  
Aged People

Background: Life expectancy is increasing all over the world, although neurodegenerative disorders might drastically affect the individual activity of aged people. Of those, Alzheimer’s Disease (AD) is one of the most social-cost age-linked diseases of industrialized countries. To date, retinal diseases seem to be more common in the developing world and characterize principally aged people. Agerelated Macular Degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with AD, including stress stimuli such as oxidative stress, inflammation and amyloid formations. Method: In both diseases, the detrimental intra/extra-cellular deposits have many similarities. Aging, hypercholesterolemia, hypertension, obesity, arteriosclerosis and smoking are risk factors to develop both diseases. Cellular aging routes have similar organelle and signaling patterns in retina and brain. The possibility to find out new research strategies represent a step forward to disclose potential treatment for both of them. Essential trace metals play critical roles in both physiological and pathological condition of retina, optic nerve and brain, by influencing metabolic processes chiefly upon complex multifactorial pathogenesis. Conclusion: Hence, this review addresses current knowledge about some up-to-date investigated essential trace metals associated with AD and AMD. Changes in the levels of systemic and ocular fluid essential metals might reflect the early stages of AMD, possibly disclosing neurodegeneration pathways shared with AD, which might open to potential early detection.

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