scholarly journals Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer's disease

2021 ◽  
Author(s):  
NANAKA KANESHIRO ◽  
KOMAI MASATO ◽  
RYOSUKE IMAOKA ◽  
ATSUYA IKEDA ◽  
YUJI KAMIKUBO ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Early Stage ◽  
Amyloid Β ◽  
Underlying Mechanism ◽  
Membrane Fission ◽  
Cytosolic Side ◽  
Lipid Flippase ◽  
Novel Therapeutic

β-amyloid precursor protein (APP) and their metabolites are deeply involved in the development of Alzheimer's disease (AD). Upon the upregulation of β-site APP cleaving enzyme 1 (BACE1), its product, the β-carboxyl-terminal fragment of APP (βCTF), is accumulated in the early stage of sporadic AD brains. βCTF accumulation is currently considered the trigger for endosomal anomalies to form enlarged endosomes, one of the earliest pathologies in AD. However, the details of the underlying mechanism remain largely unclear. In this study, using BACE1 stably-overexpressing cells, we describe that lipid flippase subcomponent TMEM30A interacts with accumulated βCTF. Among the lipid flippases in endosomes, those composed of TMEM30A and active subcomponent ATP8A1 transports phospholipid, phosphatidylserine (PS), to the cytosolic side of the endosomes. The lipid flippase activity and cytosolic PS distribution are critical for membrane fission and vesicle transport. Intriguingly, accumulated βCTF in model cells impaired lipid flippase physiological formation and activity, along with endosome enlargement. Moreover, in the brains of AD model mice before the amyloid-β (Aβ) deposition, the TMEM30A/βCTF complex formation occurred, followed by lipid flippase dysfunction. Importantly, our novel Aβ/βCTF interacting TMEM30A-derived peptide "T-RAP" improved endosome enlargement and reduced βCTF levels. These T-RAP effects could result from the recovery of lipid flippase activity. Therefore, we propose lipid flippase dysfunction as a key pathogenic event and a novel therapeutic target for AD.

scholarly journals Binding and Transport of Amyloid-β by P-Glycoprotein: A Novel Therapeutic Target in Alzheimer's Disease

2019 ◽  
Vol 116 (3) ◽  
pp. 427a-428a
Author(s):  
Hope Holt ◽  
Elizabeth Moore ◽  
Madeline Riese ◽  
Michelle Faucett ◽  
Francisco Gonzalez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Amyloid Β ◽  
P Glycoprotein ◽  
Novel Therapeutic

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

PET Imaging of Tau Pathology and Amyloid-β, and MRI for Alzheimer’s Disease Feature Fusion and Multimodal Classification

2021 ◽  
pp. 1-18
Author(s):  
Mehdi Shojaie ◽  
Solale Tabarestani ◽  
Mercedes Cabrerizo ◽  
Steven T. DeKosky ◽  
David E. Vaillancourt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Feature Selection ◽  
Mutual Information ◽  
Feature Fusion ◽  
Early Stage ◽  
Model Performance ◽  
Amyloid Β ◽  
Feature Ranking ◽  
Promising Tool

Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition.

scholarly journals Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Qi Wang ◽  
Yinghua Chen ◽  
Benjamin Readhead ◽  
Kewei Chen ◽  
Yi Su ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Longitudinal Data ◽  
Disease Progression ◽  
Peripheral Blood ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Methylation Data ◽  
Brain Tissues

Abstract Background While Alzheimer’s disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention. Methods We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters). Results When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances. Conclusions Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

P4-241: Pathogenesis of intracellular amyloid beta-protein 42 and P53: A novel therapeutic target in Alzheimer's disease

2006 ◽  
Vol 2 ◽  
pp. S588-S588
Author(s):  
Yasumasa Ohyagi ◽  
Katsue Miyoshi ◽  
Ma Linqing ◽  
Kyoko Motomura ◽  
Takeshi Tabira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Therapeutic Target ◽  
Amyloid Beta Protein ◽  
Novel Therapeutic

scholarly journals The Retinal Inner Plexiform Synaptic Layer Mirrors Grey Matter Thickness of Primary Visual Cortex with Increased Amyloid β Load in Early Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Lília Jorge ◽  
Nádia Canário ◽  
Ricardo Martins ◽  
Beatriz Santiago ◽  
Isabel Santana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Primary Visual Cortex ◽  
Early Stage ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Binding Potential ◽  
Inner Plexiform Layer ◽  
Pet Tracer

The retina may serve as putative window into neuropathology of synaptic loss in Alzheimer’s disease (AD). Here, we investigated synapse-rich layers versus layers composed by nuclei/cell bodies in an early stage of AD. In addition, we examined the associations between retinal changes and molecular and structural markers of cortical damage. We recruited 20 AD patients and 17 healthy controls (HC). Combining optical coherence tomography (OCT), magnetic resonance (MR), and positron emission tomography (PET) imaging, we measured retinal and primary visual cortex (V1) thicknesses, along with V1 amyloid β (Aβ) retention ([11C]-PiB PET tracer) and neuroinflammation ([11C]-PK11195 PET tracer). We found that V1 showed increased amyloid-binding potential, in the absence of neuroinflammation. Although thickness changes were still absent, we identified a positive association between the synapse-rich inner plexiform layer (IPL) and V1 in AD. This retinocortical interplay might reflect changes in synaptic function resulting from Aβ deposition, contributing to early visual loss.

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