scholarly journals PLCG2 as a Risk Factor for Alzheimer’s Disease

2020 ◽  
Author(s):  
Andy P. Tsai ◽  
Chuanpeng Dong ◽  
Christoph Preuss ◽  
Miguel Moutinho ◽  
Peter Bor-Chian Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Immune Cell ◽  
Missense Variant ◽  
Brain Regions ◽  
Disease Pathogenesis ◽  
Surface Receptors ◽  
The Brain ◽  
Brain Amyloid Deposition

AbstractAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for AD. Phospholipase C γ 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against AD, indicating that PLCG2 may play a role in AD pathophysiology. Here, we report that a rare missense variant in PLCG2 confers increased AD risk (p=0.047; OR=1.164 [95% CI=1.002-1.351]). Additionally, we observed that PLCG2 expression levels are increased in several brain regions of AD patients, correlating with brain amyloid deposition. This provides further evidence that PLCG2 may play an important role in AD pathophysiology. Together, our findings indicate that PLCG2 is a potential new therapeutic target for AD.

scholarly journals Deep-MEG: spatiotemporal CNN features and multiband ensemble classification for predicting the early signs of Alzheimer’s disease with magnetoencephalography

2021 ◽  
Author(s):  
Antonio Giovannetti ◽  
Gianluca Susi ◽  
Paola Casti ◽  
Arianna Mencattini ◽  
Sandra Pusil ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Ensemble Classification ◽  
The Novel ◽  
Ensemble Classifiers ◽  
Deep Convolutional Neural Networks ◽  
Early Signs ◽  
Data Representations ◽  
The Brain

AbstractIn this paper, we present the novel Deep-MEG approach in which image-based representations of magnetoencephalography (MEG) data are combined with ensemble classifiers based on deep convolutional neural networks. For the scope of predicting the early signs of Alzheimer’s disease (AD), functional connectivity (FC) measures between the brain bio-magnetic signals originated from spatially separated brain regions are used as MEG data representations for the analysis. After stacking the FC indicators relative to different frequency bands into multiple images, a deep transfer learning model is used to extract different sets of deep features and to derive improved classification ensembles. The proposed Deep-MEG architectures were tested on a set of resting-state MEG recordings and their corresponding magnetic resonance imaging scans, from a longitudinal study involving 87 subjects. Accuracy values of 89% and 87% were obtained, respectively, for the early prediction of AD conversion in a sample of 54 mild cognitive impairment subjects and in a sample of 87 subjects, including 33 healthy controls. These results indicate that the proposed Deep-MEG approach is a powerful tool for detecting early alterations in the spectral–temporal connectivity profiles and in their spatial relationships.

scholarly journals Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

2021 ◽  
Vol 22 (7) ◽  
pp. 3330
Author(s):  
Mehdi Eshraghi ◽  
Aida Adlimoghaddam ◽  
Amir Mahmoodzadeh ◽  
Farzaneh Sharifzad ◽  
Hamed Yasavoli-Sharahi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Neurological Disorder ◽  
Inflammatory Cells ◽  
Disease Pathogenesis ◽  
Current Review ◽  
The Brain ◽  
Comprehensive Discussion

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

scholarly journals Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angela M. Crist ◽  
Kelly M. Hinkle ◽  
Xue Wang ◽  
Christina M. Moloney ◽  
Billie J. Matchett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Digital Pathology ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
Biochemical Analyses ◽  
The Brain ◽  
Relevant Gene ◽  
Tau Expression

AbstractSelective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice

2021 ◽  
pp. 153537022110568
Author(s):  
Natalia V Bobkova ◽  
Daria Y Zhdanova ◽  
Natalia V Belosludtseva ◽  
Nikita V Penkov ◽  
Galina D Mironova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Memory ◽  
Intranasal Administration ◽  
Brain Structures ◽  
Brain Regions ◽  
Dependent Manner ◽  
Behavioral Experiments ◽  
Hippocampal Cell Culture ◽  
The Brain

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.

scholarly journals Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Laurence Barrier ◽  
Bernard Fauconneau ◽  
Anastasia Noël ◽  
Sabrina Ingrand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neuronal Death ◽  
Time Course ◽  
Neuronal Loss ◽  
Brain Regions ◽  
App Processing ◽  
Ceramide Accumulation ◽  
The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

scholarly journals Genetic analyses of SERPINA5 in Alzheimer’s disease

2021 ◽  
Author(s):  
Billie J. Matchett ◽  
Sarah J. Lincoln ◽  
Matt Baker ◽  
Nikoleta Tamvaka ◽  
Janisse Cabrera-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Age Of Onset ◽  
Positive Family History ◽  
Neuronal Loss ◽  
Missense Variant ◽  
Brain Regions ◽  
Allelic Frequency ◽  
Genomic Databases

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

scholarly journals Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

2021 ◽  
pp. 1-14
Author(s):  
Stefanie A.G. Black ◽  
Anastasiia A. Stepanchuk ◽  
George W. Templeton ◽  
Yda Hernandez ◽  
Tomoko Ota ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Blood Leukocytes ◽  
Peripheral Blood Mononuclear ◽  
The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Graph Theory-Based Brain Network Connectivity Analysis and Classification of Alzheimer’s Disease

2021 ◽  
Author(s):  
A. Thushara ◽  
C. Ushadevi Amma ◽  
Ansamma John
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Graph Theory ◽  
Neurodegenerative Disorder ◽  
Brain Networks ◽  
Network Connectivity ◽  
Brain Regions ◽  
Brain Network ◽  
Fiber Tracts ◽  
The Brain

Alzheimer’s Disease (AD) is basically a progressive neurodegenerative disorder associated with abnormal brain networks that affect millions of elderly people and degrades their quality of life. The abnormalities in brain networks are due to the disruption of White Matter (WM) fiber tracts that connect the brain regions. Diffusion-Weighted Imaging (DWI) captures the brain’s WM integrity. Here, the correlation betwixt the WM degeneration and also AD is investigated by utilizing graph theory as well as Machine Learning (ML) algorithms. By using the DW image obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, the brain graph of each subject is constructed. The features extracted from the brain graph form the basis to differentiate between Mild Cognitive Impairment (MCI), Control Normal (CN) and AD subjects. Performance evaluation is done using binary and multiclass classification algorithms and obtained an accuracy that outperforms the current top-notch DWI-based studies.

scholarly journals Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

2020 ◽  
Vol 21 (21) ◽  
pp. 8338
Author(s):  
Kimberley D. Bruce ◽  
Maoping Tang ◽  
Philip Reigan ◽  
Robert H. Eckel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipoprotein Lipase ◽  
Genetic Variants ◽  
Disease Risk ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Direct Role ◽  
The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

scholarly journals The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1520
Author(s):  
Gabriel Santpere ◽  
Marco Telford ◽  
Pol Andrés-Benito ◽  
Arcadi Navarro ◽  
Isidre Ferrer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Human Herpesvirus ◽  
Brain Regions ◽  
Specific Cell ◽  
Human Herpesvirus 6 ◽  
Detection Techniques ◽  
Herpesvirus 6 ◽  
The Brain

The human herpesvirus 6 (HHV‐6) ‐A and ‐B are two dsDNA beta‐herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV‐6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV‐6detection in the nervous system. The effort of more than three decades of researching HHV‐6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV‐6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV‐6 in the brains of patients with Alzheimer’s disease in light of availableevidence.

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