scholarly journals The landscape of metabolic brain alterations in Alzheimer's disease

2021 ◽  
Author(s):  
Richa Batra ◽  
Matthias Arnold ◽  
Maria Woerheide ◽  
Mariet Allen ◽  
Xue Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Metabolism ◽  
Temporal Cortex ◽  
Interactive Network ◽  
Dorsolateral Prefrontal ◽  
Amyloid Load ◽  
Reference Map ◽  
Β Amyloid ◽  
Multi Center Study

We present a comprehensive reference map of metabolic brain changes in Alzheimer's disease (AD). In a multi-center study within the Accelerating Medicines Partnership in AD, we metabolically profiled 500 samples from the dorsolateral prefrontal cortex (DLPFC) and 83 samples from the temporal cortex (TCX). In the DLPFC, 298 metabolites were correlated with AD-related traits, including late-life cognitive performance and neuropathological β-amyloid and tau tangle burden. Out of these 298 metabolites, 35 replicated in TCX and a previous study. A conditional analysis suggests that metabolic associations with tangle burden were largely independent of β-amyloid load in the brain. Our results provide evidence of brain alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways. In a detailed investigation of the glutamate/GABA neurotransmitter pathway, we demonstrate how integration of complementary omics data can provide a comprehensive view of dysregulated biochemical processes. All associations are available as an interactive network at https://omicscience.org/apps/brainmwas/.

scholarly journals Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Peter Parbo ◽  
Lasse Stensvig Madsen ◽  
Rola Ismail ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Mean Diffusivity ◽  
Brain Inflammation ◽  
Translocator Protein ◽  
Inverse Association ◽  
Neurofilament Light ◽  
Amyloid Load ◽  
Β Amyloid

Abstract Background Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. Methods Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics. Results Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping. Conclusion We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.

“Risk factors” and histopathological hallmark lesions of Alzheimer's disease including β-amyloid load in aging and dementia

2000 ◽  
Vol 21 ◽  
pp. 264
Author(s):  
Irina I. Alafuzoff ◽  
Mia Pirskanen ◽  
Arto Mannermaa ◽  
Seppo Helisalmi ◽  
Hilka Souininen
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Load ◽  
Β Amyloid

P4-381 Reduction of β-amyloid load in Alzheimer's disease transgenic mice by competitive blocking of β-amyloid binding to apolipoprotein E

2004 ◽  
Vol 25 ◽  
pp. S583
Author(s):  
Thomas Wisniewski ◽  
Joanna Pankiewicz ◽  
Henrieta Scholtzova ◽  
Stephen D. Schmidt ◽  
Paul M. Mathews ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Apolipoprotein E ◽  
Amyloid Load ◽  
Β Amyloid

Аnticholinesterase and antioxidant activity of new binary conjugates of (с)-carbolines

2019 ◽  
Vol 484 (1) ◽  
pp. 104-108
Author(s):  
G. F. Makhaeva ◽  
E. F. Shevtsova ◽  
N. P. Boltneva ◽  
N. V. Kovaleva ◽  
E. V. Rudakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Activity ◽  
Anticholinesterase Activity ◽  
Amyloid Aggregation ◽  
Varying Length ◽  
Β Amyloid ◽  
New Compounds

This study presents the synthesis of binary tetrohydro-γ-carbolines with ditriazol spacers of varying length, which exhibit anticholinesterase and antioxidant activity, as compared to the original Dimebon prototype. Anticholinesterase activity suggests the potential ability of the new compounds to block β-amyloid aggregation induced by anticholinesterase, making them promising candidates for further research preparations for the treatment of Alzheimer's disease. Particular attention should be paid to the conjugate with an intertriazol hexamethylene spacer, which can be regarded as the leading compound in this series.

Alzheimer’s Disease: Erythrocyte 2,3-diphosphoglycerate Content and Circulating Erythropoietin

2019 ◽  
Vol 16 (9) ◽  
pp. 834-835
Author(s):  
Petter Järemo ◽  
Alenka Jejcic ◽  
Vesna Jelic ◽  
Tasmin Shahnaz ◽  
Homira Behbahani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cell Damage ◽  
Control Group ◽  
Red Cell ◽  
Oxygen Release ◽  
Regulatory Pathways ◽  
Β Amyloid ◽  
2,3 Dpg

Background: Alzheimer’s Disease (AD) features the accumulation of β-amyloid in erythrocytes. The subsequent red cell damage may well affect their oxygen-carrying capabilities. 2,3- diphosphoglycerate (2,3-DPG) binds to the hemoglobin thereby promoting oxygen release. It is theorized that 2,3-DPG is reduced in AD and that the resulting hypoxia triggers erythropoietin (EPO) release. Methods & Objective: To explore this theory, we analyzed red cell 2,3-DPG content and EPO in AD, mild cognitive impairment, and the control group, subjective cognitive impairment. Results: We studied (i) 2,3-DPG in red cells, and (ii) circulating EPO in AD, and both markers were unaffected by dementia. Disturbances of these oxygen-regulatory pathways do not appear to participate in brain hypoxia in AD.

Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging

2019 ◽  
Vol 16 (8) ◽  
pp. 723-731 ◽  
Author(s):  
Alexander Sturzu ◽  
Sumbla Sheikh ◽  
Hubert Kalbacher ◽  
Thomas Nägele ◽  
Christopher Weidenmaier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Flow Cytometry ◽  
Transgenic Mice ◽  
Ex Vivo ◽  
Amyloid Plaques ◽  
Laser Scanning Microscopy ◽  
Β Amyloid ◽  
Curcumin Derivative

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques. Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques. Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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