NeuroDefend, a novel Chinese medicine, attenuates amyloid-β and tau pathology in experimental Alzheimer's disease models

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE 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 APOE 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). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE 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 APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE 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 APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

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

Science Translational Medicine ◽

10.1126/scitranslmed.aau6550 ◽

2019 ◽

Vol 11 (474) ◽

pp. eaau6550 ◽

Cited By ~ 65

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.

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

Nature Neuroscience ◽

10.1038/s41593-018-0332-9 ◽

2019 ◽

Vol 22 (3) ◽

pp. 401-412 ◽

Cited By ~ 233

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

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miR-16-5p is upregulated by amyloid β deposition in Alzheimer's disease models and induces neuronal cell apoptosis through direct targeting and suppression of BCL-2

Experimental Gerontology ◽

10.1016/j.exger.2020.110954 ◽

2020 ◽

Vol 136 ◽

pp. 110954 ◽

Cited By ~ 2

Author(s):

Yeong-Jin Kim ◽

So Hee Kim ◽

Yega Park ◽

Jiyu Park ◽

Jung Hoon Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Apoptosis ◽

Amyloid Β ◽

Neuronal Cell ◽

Disease Models ◽

Direct Targeting

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

Brain ◽

10.1093/brain/awz371 ◽

2019 ◽

Vol 143 (1) ◽

pp. 359-373 ◽

Cited By ~ 5

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.

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