scholarly journals Blocking the apolipoprotein E/Amyloid β interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid β and tau pathology

2013 ◽  
Vol 128 (4) ◽  
pp. 577-591 ◽  
Author(s):  
Shan Liu ◽  
Ariel Breitbart ◽  
Yanjie Sun ◽  
Pankaj D. Mehta ◽  
Allal Boutajangout ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Tau Pathology

The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

2021 ◽  
Vol 84 (6) ◽  
pp. 472-480
Author(s):  
Yulin Luo ◽  
Li Tan ◽  
Joseph Therriault ◽  
Hua Zhang ◽  
Ying Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Disease Assessment ◽  
Tau Pathology ◽  
Ε4 Allele ◽  
State Examination

<b><i>Background:</i></b> Apolipoprotein E (<i>APOE</i>) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of <i>APOE</i> ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of <i>APOE</i> ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). <b><i>Methods:</i></b> Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, <i>APOE</i> ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of <i>APOE</i> ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). <b><i>Results:</i></b> The prevalence of <i>APOE</i> ε4 is higher in EMCI and LMCI than in CN (<i>p</i> &#x3c; 0.001 for both), and in LMCI than in EMCI (<i>p</i> = 0.001). <i>APOE</i> ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (<i>p</i> &#x3c; 0.001). Subjects who had a lower CSF Aβ42 level and were <i>APOE</i> ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. <b><i>Conclusions:</i></b> An <i>APOE</i> ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that <i>APOE</i> ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

O3-01-01: Amyloid-β protofibrils are linked to cognitive impairment in Alzheimer's disease transgenic mice

2008 ◽  
Vol 4 ◽  
pp. T157-T157
Author(s):  
Anna Lord ◽  
Hillevi Englund ◽  
Fredrik Clausen ◽  
Lars Hillered ◽  
Frida Ekholm Pettersson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Transgenic Mice ◽  
Amyloid Β

scholarly journals Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease

2019 ◽  
Vol 11 (474) ◽  
pp. eaau6550 ◽  
Author(s):  
Brendan P. Lucey ◽  
Austin McCullough ◽  
Eric C. Landsness ◽  
Cristina D. Toedebusch ◽  
Jennifer S. McLeland ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Eye Movement ◽  
Single Channel ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Rapid Eye Movement ◽  
Tau Pathology ◽  
Potential Marker

In Alzheimer’s disease (AD), deposition of insoluble amyloid-β (Aβ) is followed by intracellular aggregation of tau in the neocortex and subsequent neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment. By the time even the earliest clinical symptoms are detectable, Aβ accumulation is close to reaching its peak and neocortical tau pathology is frequently already present. The period in which AD pathology is accumulating in the absence of cognitive symptoms represents a clinically relevant time window for therapeutic intervention. Sleep is increasingly recognized as a potential marker for AD pathology and future risk of cognitive impairment. Previous studies in animal models and humans have associated decreased non–rapid eye movement (NREM) sleep slow wave activity (SWA) with Aβ deposition. In this study, we analyzed cognitive performance, brain imaging, and cerebrospinal fluid (CSF) AD biomarkers in participants enrolled in longitudinal studies of aging. In addition, we monitored their sleep using a single-channel electroencephalography (EEG) device worn on the forehead. After adjusting for multiple covariates such as age and sex, we found that NREM SWA showed an inverse relationship with AD pathology, particularly tauopathy, and that this association was most evident at the lowest frequencies of NREM SWA. Given that our study participants were predominantly cognitively normal, this suggested that changes in NREM SWA, especially at 1 to 2 Hz, might be able to discriminate tau pathology and cognitive impairment either before or at the earliest stages of symptomatic AD.

scholarly journals Elevated Aβ and Apolipoprotein E in AβPP Transgenic Mice and Its Relationship to Amyloid Accumulation in Alzheimer’s Disease

2000 ◽  
Vol 6 (5) ◽  
pp. 430-439 ◽  
Author(s):  
Yu-Min Kuo ◽  
Fiona Crawford ◽  
Michael Mullan ◽  
Tyler A. Kokjohn ◽  
Mark R. Emmerling ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Apolipoprotein E ◽  
Amyloid Accumulation

scholarly journals Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

2019 ◽  
Vol 22 (3) ◽  
pp. 401-412 ◽  
Author(s):  
Evandro F. Fang ◽  
Yujun Hou ◽  
Konstantinos Palikaras ◽  
Bryan A. Adriaanse ◽  
Jesse S. Kerr ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Tau Pathology

scholarly journals N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

2019 ◽  
Vol 116 (47) ◽  
pp. 23426-23436 ◽  
Author(s):  
Min Hee Park ◽  
Misun Lee ◽  
Geewoo Nam ◽  
Mingeun Kim ◽  
Juhye Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Causative Factor ◽  
Central Feature ◽  
Microglial Phagocytosis ◽  
Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

scholarly journals Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 359-373 ◽  
Author(s):  
Christopher D Morrone ◽  
Paolo Bazzigaluppi ◽  
Tina L Beckett ◽  
Mary E Hill ◽  
Margaret M Koletar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Spatial Memory ◽  
Regional Differences ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Barnes Maze ◽  
Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice

1997 ◽  
Vol 3 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Martin Citron ◽  
David Westaway ◽  
Weiming Xia ◽  
George Carlson ◽  
Thekla Diehl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Transfected Cells ◽  
Β Protein

scholarly journals New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

2020 ◽  
Vol 52 (4) ◽  
pp. 556-568 ◽  
Author(s):  
Sun Ah Park ◽  
Song Mi Han ◽  
Chae Eun Kim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Response ◽  
Amyloid Β ◽  
Clinical Severity ◽  
Intercellular Adhesion Molecule ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Protein Clearance ◽  
New Biomarkers

Abstract Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer’s disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration- and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD.

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