scholarly journals PGRN Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

2020 ◽  
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Xi-Peng Cao ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tgf Β1

Abstract Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

scholarly journals Pgrn Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

2020 ◽  
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Xi-Peng Cao ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tgf Β1

Abstract Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

scholarly journals PGRN alleviates cerebral amyloid-β burden and cognitive impairments via mediating neuroinflammation

2020 ◽  
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Xi-Peng Cao ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tgf Β1

Abstract Background Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were increased with tau-related neurodegeneration. PGRN was positively linked with neuroinflammatory markers associated with tau pathologies (TN+). In TN + population, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions These preliminary findings supported that PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

scholarly journals Mild behavioral impairment correlates of cognitive impairments in older adults without dementia: mediation by amyloid pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Sun ◽  
Wei Xu ◽  
Ke-Liang Chen ◽  
Xue-Ning Shen ◽  
Lan Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Amyloid Pet ◽  
Amyloid Burden ◽  
Behavioral Impairment ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Language Functions ◽  
Β Amyloid

AbstractThe relationship between mild behavioral impairment (MBI) and Alzheimer’s disease (AD) is intricate and still not well investigated. The purpose of the study is to examine the roles of the AD imaging pathologies in modulating the associations of MBI with cognitive impairments. We analyzed 1129 participants (563 [49.86%] female), who had measures of Neuropsychiatric Inventory Questionnaire (NPI-Q), cognition, and amyloid PET AD biomarkers from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We assess the longitudinal neuropathological and clinical correlates of baseline MBI via linear mixed effects and Cox proportional hazard models. The mediation analyses were used to test the mediation effects of AD pathologies on cognition. We found that MBI was associated with worse global cognition as represented by Mini-Mental State Examination (MMSE) (p < 0.001), and higher β-amyloid burden (p < 0.001). β-amyloid partially mediated the effects of MBI on cognition with the mediation percentage varied from 14.67 to 40.86% for general cognition, memory, executive, and language functions for non-dementia individuals. However, no significant associations were discovered between MBI and tau burden or neurodegeneration. Furthermore, longitudinal analyses revealed that individuals with MBI had a faster increase in brain amyloid burden (p < 0.001) and a higher risk of clinical conversion (HR = 2.42, 95% CI = 1.45 to 4.01 p < 0.001). In conclusion, MBI could be an imperative prediction indicator of clinical and pathological progression. In addition, amyloid pathologies might partially mediate the influences of MBI on cognitive impairments and AD risk.

scholarly journals Target-driven supramolecular self-assembly for selective amyloid-β photooxygenation against Alzheimer's disease

2020 ◽  
Vol 11 (40) ◽  
pp. 11003-11008
Author(s):  
Zhenqi Liu ◽  
Mengmeng Ma ◽  
Dongqin Yu ◽  
Jinsong Ren ◽  
Xiaogang Qu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photodynamic Therapy ◽  
Self Assembly ◽  
Amyloid Β ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid

Photo-oxygenation of β-amyloid (Aβ) has been considered an efficient way to inhibit Aβ aggregation in Alzheimer's disease (AD). We present the first example of Aβ-responsive photodynamic therapy to treatment of AD by using PKNPs self-assemblies.

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.

scholarly journals Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

2005 ◽  
Vol 171 (1) ◽  
pp. 87-98 ◽  
Author(s):  
W. Haung Yu ◽  
Ana Maria Cuervo ◽  
Asok Kumar ◽  
Corrinne M. Peterhoff ◽  
Stephen D. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Survival ◽  
Mammalian Target Of Rapamycin ◽  
Amyloid Peptide ◽  
Survival Pathways ◽  
Secretase Activity ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Β Amyloid Peptide

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

scholarly journals P-tau and neurodegeneration mediate the effect of β-amyloid on cognition in non-demented elders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ling-Zhi Ma ◽  
Hao Hu ◽  
Zuo-Teng Wang ◽  
Ya-Nan Ou ◽  
Qiang Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Mediating Effect ◽  
Total Effect ◽  
Independent Effect ◽  
Carrier Status ◽  
Mediation Effects ◽  
Β Amyloid ◽  
The Impact

Abstract Background There are many pathological changes in the brains of Alzheimer’s disease (AD) patients. For many years, the mainstream view on the pathogenesis of AD believes that β-amyloid (Aβ) usually acts independently in addition to triggering functions. However, the evidence now accumulating indicates another case that these pathological types have synergies. The objective of this study was to investigate whether effects of Aβ pathology on cognition were mediated by AD pathologies, including tau-related pathology (p-tau), neurodegeneration (t-tau, MRI measurements), axonal injury (NFL), synaptic dysfunction (neurogranin), and neuroinflammation (sTREM2, YKL-40). Methods Three hundred seventy normal controls (CN) and 623 MCI patients from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) database were recruited in this research. Linear mixed-effects models were used to evaluate the associations of baseline Aβ with cognitive decline and biomarkers of several pathophysiological pathways. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition. Results Tau-related pathology, neurodegeneration, neuroinflammation are correlated with the concentration of Aβ, even in CN participants. The results show that age, gender, and APOE ε4 carrier status have a moderating influence on some of these relationships. There is a stronger association of Aβ with biomarkers and cognitive changes in the elderly and females. In CN group, Aβ pathology is directly related to poor cognition and has no mediating effect (p < 0.05). In mild cognitive impairment, tau-related pathology (26.15% of total effect) and neurodegeneration (14.8% to 47.0% of total effect) mediate the impact of Aβ on cognition. Conclusions In conclusion, early Aβ accumulation has an independent effect on cognitive decline in CN and a tau, neurodegeneration-dependent effect in the subsequent cognitive decline in MCI patients.

Distance-based β-amyloid protein detection on PADs for scanning and subsequent follow up of Alzheimer’s disease in human urine sample

The Analyst ◽  
2022 ◽  
Author(s):  
Kawin Khachornsakkul ◽  
Anongnat Tiangtrong ◽  
Araya Suwannasom ◽  
Wuttichai Sangkharoek ◽  
Opor Jamjumrus ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Urine ◽  
Protein Detection ◽  
Protein Quantification ◽  
Amyloid Protein ◽  
Human Urine Sample ◽  
Amyloid Aβ ◽  
Β Amyloid

We report on the first development of a simple distance-based β-amyloid (Aβ) protein quantification using paper-based devices (dPADs) to screen for Alzheimer’s disease (AD) and to subsequently follow up on...

scholarly journals Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

2020 ◽  
Vol 6 (33) ◽  
pp. eabb9036
Author(s):  
Bradlee L. Heckmann ◽  
Brett J. W. Teubner ◽  
Emilio Boada-Romero ◽  
Bart Tummers ◽  
Clifford Guy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Disease ◽  
Memory Impairment ◽  
Memory Loss ◽  
Tau Hyperphosphorylation ◽  
Primary Microglia ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

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