Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

AbstractThe repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

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The Role of Eicosanoids in Alzheimer’s Disease

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16142560 ◽

2019 ◽

Vol 16 (14) ◽

pp. 2560 ◽

Cited By ~ 4

Author(s):

Roger G. Biringer

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Biological Functions ◽

Tau Pathology ◽

Cellular Processes ◽

Eicosanoid Metabolism ◽

Underlying Mechanisms

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders known. Estimates from the Alzheimer’s Association suggest that there are currently 5.8 million Americans living with the disease and that this will rise to 14 million by 2050. Research over the decades has revealed that AD pathology is complex and involves a number of cellular processes. In addition to the well-studied amyloid-β and tau pathology, oxidative damage to lipids and inflammation are also intimately involved. One aspect all these processes share is eicosanoid signaling. Eicosanoids are derived from polyunsaturated fatty acids by enzymatic or non-enzymatic means and serve as short-lived autocrine or paracrine agents. Some of these eicosanoids serve to exacerbate AD pathology while others serve to remediate AD pathology. A thorough understanding of eicosanoid signaling is paramount for understanding the underlying mechanisms and developing potential treatments for AD. In this review, eicosanoid metabolism is examined in terms of in vivo production, sites of production, receptor signaling, non-AD biological functions, and known participation in AD pathology.

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Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190807160137 ◽

2019 ◽

Vol 18 (7) ◽

pp. 566-577 ◽

Cited By ~ 4

Author(s):

Xinxin Fu ◽

Tingting Qin ◽

Jiayu Yu ◽

Jie Jiao ◽

Zhanqiang Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Fat Diet ◽

Trifolium Pratense ◽

Amyloid Β ◽

Cognitive Disorder ◽

Mechanism Study ◽

High Fat ◽

Neuroprotective Effects ◽

Underlying Mechanisms

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin. Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

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Distinct network topology in Alzheimer’s disease and behavioral variant frontotemporal dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00752-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Adeline Su Lyn Ng ◽

Juan Wang ◽

Kwun Kei Ng ◽

Joanna Su Xian Chong ◽

Xing Qian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Network Topology ◽

Neuropsychiatric Symptoms ◽

Brain Network ◽

Salience Network ◽

Behavioral Variant Frontotemporal Dementia ◽

Control Networks ◽

And Control

Abstract Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

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