Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery

Liu, Yuhui; Wang, Ye‐Ran; Xiang, Yang; Zhou, Hua‐Dong; Giunta, Brian; Mañucat-Tan, Noralyn B.; Tan, Jun; Zhou, Xin‐Fu; Wang, Yanjiang

doi:10.1007/s12035-014-8694-9

Cited by 80 publications

(49 citation statements)

References 56 publications

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“…Approaches to improve peripheral Aβ clearance via enhancing phagocytosis 45 , proteolytic degradation and excretion 155,156 , and identification of rejuvenation factors in blood 68 , are other promising systemic therapeutic strategies for AD 157 .…”

Section: Blood Rna Profilesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Blood Rna Profilesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…; Liu et al . ). Thus, an important issue when assessing the functional role of neuroinflammatory receptors in AD is whether Aβ‐binding causes Aβ degradation (i.e., phagocytosis) and/or an inflammatory response.…”

Section: Neuroinflammation In Admentioning

confidence: 97%

“…Although there is evidence of extracellular Ab clearance with passive immunization, side effects include edema and cerebral microhemorrhage, identified by amyloidrelated imaging abnormalities (Sperling et al 2011;Sperling et al 2012). It has also been proposed that some of the negative side effects from Fc-dependent Ab phagocytosis may be the result of a pro-inflammatory response (Fuller et al 2014;Liu et al 2014). Thus, an important issue when assessing the functional role of neuroinflammatory receptors in AD is whether Ab-binding causes Ab degradation (i.e., phagocytosis) and/or an inflammatory response.…”

Section: Neuroinflammatory Receptors In Admentioning

confidence: 99%

APOE‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

Tai

Ghura

Koster

et al. 2015

Journal of Neurochemistry

130

118

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Chronic glial activation and neuroinflammation induced by the amyloid-b peptide (Ab) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Ab-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Ab-independent neuroinflammation, data for APOE-modulated Ab-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Ab-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38a) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation.

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“…Several different approaches are now being developed in order to circumvent these problems, namely by altering the isotype of Aβ-specific antibodies in order to prevent the risk of Fc receptor-mediated over activation of microglia and the risk of vasogenic edema (Adolfsson et al, 2012). However, to date, no active or passive immunization approach has produced positive results on memory and cognition (Liu et al, 2015). Nevertheless, it is increasingly evident, from data presented in different studies, that immune cells play a critical role in the pathophysiology of AD.…”

Section: The Impact Of the Immune System On Brain Function In Admentioning

confidence: 99%

Insights on the pathophysiology of Alzheimer's disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system

Mesquita

Ferreira

Sousa

et al. 2016

Neuroscience & Biobehavioral Reviews

129

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Alzheimer's disease (AD) is the most common form of dementia, whose prevalence is growing along with the increased life expectancy. Although the accumulation and deposition of amyloid beta (Aβ) peptides in the brain is viewed as one of the pathological hallmarks of AD and underlies, at least in part, brain cell dysfunction and behavior alterations, the etiology of this neurodegenerative disease is still poorly understood. Noticeably, increased amyloid load is accompanied by marked inflammatory alterations, both at the level of the brain parenchyma and at the barriers of the brain. However, it is debatable whether the neuroinflammation observed in aging and in AD, together with alterations in the peripheral immune system, are responsible for increased amyloidogenesis, decreased clearance of Aβ out of the brain and/or the marked deficits in memory and cognition manifested by AD patients. Herein, we scrutinize some important traits of the pathophysiology of aging and AD, focusing on the interplay between the amyloidogenic pathway, neuroinflammation and the peripheral immune system.

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Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery

Cited by 80 publications

References 56 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

APOE‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

Insights on the pathophysiology of Alzheimer's disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system

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