scholarly journals Alzheimer’s Disease: New Data Highlight Nonneuronal Cell Types and the Necessity for Presymptomatic Prevention Strategies

2014 ◽  
Vol 75 (7) ◽  
pp. 553-557 ◽  
Author(s):  
Sam Gandy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Prevention Strategies

scholarly journals Single-cell transcriptomic analysis elucidates APOE genotype specific changes across cell types in two brain regions in Alzheimer’s disease

2021 ◽  
Author(s):  
Stella Belonwu ◽  
Yaqiao Li ◽  
Daniel Bunis ◽  
Arjun Arkal Rao ◽  
Caroline Warly Solsberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Apoe Genotype ◽  
Cell Types ◽  
Brain Regions ◽  
Single Cell Level ◽  
Cell Level ◽  
Single Nucleus

Abstract Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. Here, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT)

2021 ◽  
pp. 1-11
Author(s):  
N. Costa ◽  
M. Mounié ◽  
A. Pagès ◽  
H. Derumeaux ◽  
T. Rapp ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cost Effectiveness ◽  
Community Dwelling ◽  
Z Score ◽  
Prevention Strategies ◽  
Group Setting ◽  
The Cost ◽  
Preventive Trial ◽  
Score Point

BACKGROUND: To date, no curative treatment is available for Alzheimer’s disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems. Objective: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo. Design: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group. Setting: Participants were recruited and included in 13 memory centers in France and Monaco. Participants: Community-dwelling subject aged 70 years and older were followed during 3 years. Interventions: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone. Measurement: Direct medical and non-medical costs were calculated from a payer’s perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria. Results: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point. Conclusion: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

Update on Alzheimer's Disease Therapy and Prevention Strategies

2017 ◽  
Vol 68 (1) ◽  
pp. 413-430 ◽  
Author(s):  
W. Vallen Graham ◽  
Alessandra Bonito-Oliva ◽  
Thomas P. Sakmar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prevention Strategies ◽  
Disease Therapy

scholarly journals Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1572-1587 ◽  
Author(s):  
John D Arena ◽  
Douglas H Smith ◽  
Edward B Lee ◽  
Garrett S Gibbons ◽  
David J Irwin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Cell Types ◽  
Tau Pathology ◽  
Post Translational Modifications ◽  
Age Related ◽  
History Of ◽  
Severe Tbi

Abstract Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer’s disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer’s disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer’s disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer’s disease and ageing may rest solely on the pattern and distribution of pathology.

Clinical relevance of the neurotrophins and their receptors

2006 ◽  
Vol 110 (2) ◽  
pp. 175-191 ◽  
Author(s):  
Shelley J. Allen ◽  
David Dawbarn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Disease Process ◽  
Neuronal Cell ◽  
Cell Types ◽  
Dependent Manner ◽  
Disease States ◽  
Neuronal Tissues

The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.

scholarly journals TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models

2015 ◽  
Vol 212 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Taylor R. Jay ◽  
Crystal M. Miller ◽  
Paul J. Cheng ◽  
Leah C. Graham ◽  
Shane Bemiller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Mouse Models ◽  
Myeloid Cells ◽  
Cell Types ◽  
Targeted Therapeutics ◽  
Amyloid Deposits ◽  
Inflammatory Macrophages

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2’s involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2+ macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

scholarly journals Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.

1996 ◽  
Vol 44 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
P J McMillan ◽  
J B Leverenz ◽  
P Poorkaj ◽  
G D Schellenberg ◽  
D M Dorsa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Basal Forebrain ◽  
Cell Types ◽  
Hybridization Histochemistry ◽  
In Situ Hybridization Histochemistry ◽  
A Cell ◽  
The Brain

Mutations in the STM2 gene cause familial Alzheimer's disease (AD) in Volga Germans. To understand the function of this protein and how mutations lead to AD, it is important to determine which cell types in the brain express this gene. In situ hybridization histochemistry indicates that STM2 expression in the human brain is widespread and is primarily neuronal. In addition, STM2 mRNA is expressed in a cell line with neuronal origins. Quantification of the level of expression of the STM2 message in the basal forebrain, frontal cortex, and hippocampus reveals a significant decrease in AD-affected subjects compared to normal age-matched controls. These data suggest that downregulation of neuronal STM2 gene expression may be involved in the progression of AD.

scholarly journals Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bing Bai ◽  
David Vanderwall ◽  
Yuxin Li ◽  
Xusheng Wang ◽  
Suresh Poudel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Splicing ◽  
Biomarker Discovery ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
Cell Types ◽  
Synaptic Function ◽  
Mitochondrial Activity ◽  
Cellular Markers

AbstractMass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer’s disease (AD). Here we review the advances and limitations in historic and recent AD proteomic research. Complementary to genetic mapping, proteomic studies not only validate canonical amyloid and tau pathways, but also uncover novel components in broad protein networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, and mitochondrial activity. Meta-analysis of seven deep datasets reveals 2,698 differentially expressed (DE) proteins in the landscape of AD brain proteome (n = 12,017 proteins/genes), covering 35 reported AD genes and risk loci. The DE proteins contain cellular markers enriched in neurons, microglia, astrocytes, oligodendrocytes, and epithelial cells, supporting the involvement of diverse cell types in AD pathology. We discuss the hypothesized protective or detrimental roles of selected DE proteins, emphasizing top proteins in “amyloidome” (all biomolecules in amyloid plaques) and disease progression. Comprehensive PTM analysis represents another layer of molecular events in AD. In particular, tau PTMs are correlated with disease stages and indicate the heterogeneity of individual AD patients. Moreover, the unprecedented proteomic coverage of biofluids, such as cerebrospinal fluid and serum, procures novel putative AD biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier to link genotype, proteotype, and phenotype, accelerating the development of improved AD models and treatment strategies.

scholarly journals Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

2018 ◽  
Author(s):  
Nisha Rathore ◽  
Sree Ranjani Ramani ◽  
Homer Pantua ◽  
Jian Payandeh ◽  
Tushar Bhangale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Disease Risk ◽  
Missense Variant ◽  
Cell Types ◽  
Glycoprotein B ◽  
Receptor Alpha ◽  
Hsv 1

AbstractPaired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

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