Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

Frenkel, Dan; Wilkinson, Kim; Zhao, Lingzhi; Hickman, Suzanne E.; Means, Terry K.; Puckett, Lindsay; Farfara, Dorit; Kingery, Nathan D.; Weiner, Howard L.; Khoury, Joseph El

doi:10.1038/ncomms3030

Cited by 181 publications

(166 citation statements)

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“…The failure to clear Aβ (especially Aβ 42 ) is an important cause of sporadic AD, which accounts for 99% of AD cases. Understanding how Aβ is physiologically cleared from the brain is, therefore, essential.…”

Section: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

“…Accumulations of Aβ in the periphery can similarly be phagocytosed by monocytes and neutrophils in the blood, and by macrophages in tissues 41 . Of note, in transgenic mice with AD, expression of Aβ scavenger receptors and Aβ-degrading enzymes in circulating mononuclear phagocytes decreases substantially as these mice age 42 , and the phagocytic functions of these cells are impaired in both mice and humans with AD [43][44][45] . Infusion of monocytes derived from peripheral human umbilical cord blood reduces the Aβ burden and improves cognitive deficits in a mouse model of AD 46 , implying that peripheral mononuclear phagocytes have an important role in Aβ clearance.…”

Section: Disorders Of Systemic Immunitymentioning

confidence: 99%

“…Aβ levels (in both peripheral tissues and the brain) are known to be lower in cognitively normal elderly individuals than in patients with AD (TABLE 1). The accumulation of Aβ aggregates in elderly patients with and without AD is an important factor that could influence the ratio of Aβ 42 to Aβ 40 in both brain and periphery. Given that skeletal muscle represents about one-quarter of body weight in humans and is just one of many peripheral sources of Aβ, peripherally derived Aβ is likely to represent a substantial proportion of the total.…”

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confidence: 99%

“…First, Aβ 42 , which is the most aggregation-prone and most neurotoxic form of Aβ, is the dominant molecular species in the brain, whereas Aβ 40 is dominant in the periphery, although the mechanism underlying this difference is still unclear. Differential expression of APP isoforms in the brain and periphery is one possible explanation.…”

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confidence: 99%

“…The aggregation (oligomerization and fibrillogenesis) of Aβ peptides is determined by the relative proportions of Aβ species, their concentrations, the pH, temperature and ionic strength of solution, and incubation time 16 . In the periphery, therefore, an increased proportion of Aβ 40 might lead to sequestration of Aβ 42 in a stable mixed formation, thereby preventing its oligomerization and aggregation 17 , whereas an increased proportion of Aβ 42 in the brain might render Aβ 42 susceptible to aggregation.…”

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confidence: 99%

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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: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

Section: Disorders Of Systemic Immunitymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

et al. 2017

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Genomics of Alzheimer Disease

et al. 2016

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IMPORTANCE To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy. OBSERVATIONS Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the amyloid precursor protein (APP) gene. A detrimental APP mutation at the β-secretase cleavage site linked to early-onset AD found in a Swedish pedigree enhances Aβ production, in contrast to a beneficial mutation 2 residues away in APP that reduces Aβ production and protects against the onset of sporadic AD. A number of common variants associated with late-onset AD have been identified including apolipoprotein E, BIN1, ABC7, PICALM, MS4A4E/MS4A6A, CD2Ap, CD33, EPHA1, CLU, CR1, and SORL1. One or 2 copies of the apolipoprotein E ε4 allele are a major risk factor for late-onset AD. With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved with a downregulation of Aβ42-specific effector (Thl, Th17, and Th2) cell responses at later immunization times. DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and its cytokine interleukin 10, resulting in downregulation of T effectors. CONCLUSIONS AND RELEVANCE Mutations in APP and PS-1 and PS-2 genes that are associated with early-onset, autosomal, dominantly inherited AD, in addition to the at-risk gene polymorphisms responsible for late-onset AD, all indicate a direct and early role of Aβ in the pathogenesis of AD. A translational result of genomic research has been Aβ-reducing therapies including DNA Aβ42 vaccination as a promising approach to delay or prevent this disease.

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Neurobiological, Psychosocial, and Behavioral Mechanisms Mediating Associations Between Physical Activity and Psychiatric Symptoms in Youth in the Netherlands

et al. 2023

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ImportanceUnderstanding the mechanisms by which physical activity is associated with a lower risk of psychiatric symptoms may stimulate the identification of cost-efficient strategies for preventing and treating mental illness at early life stages.ObjectiveTo examine neurobiological, psychosocial, and behavioral mechanisms that mediate associations of physical activity with psychiatric symptoms in youth by testing an integrated model.Design, setting, and participantsGeneration R is an ongoing prospective population-based cohort study collecting data from fetal life until young adulthood in a multiethnic urban population in the Netherlands. Pregnant women living in Rotterdam with an expected delivery date between April 2002 and January 2006 were eligible for participation along with their children born during this time. Data were collected at a single research center in the Erasmus Medical Center Sophia Children’s Hospital. For the current study, data were analyzed from 4216 children with complete data on both exposure and outcome at ages 6, 10, and 13 years. Data were analyzed from January 2021 to November 2022.ExposuresPhysical activity was ascertained at age 6 years (visit 1) via parent report and included weekly frequency and duration of walking or cycling to or from school, physical education at school, outdoor play, swimming, and sports participation.Main Outcomes and MeasuresPsychiatric symptoms (internalizing and externalizing symptoms) were assessed at age 6 years (visit 1) and at age 13 years (visit 3) using the Child Behavior Checklist. Several mechanisms were explored as mediators, measured at age 10 years (visit 2). Neurobiological mechanisms included total brain volume, white matter microstructure, and resting-state connectivity assessed using a 3-T magnetic resonance imaging scanner. Psychosocial mechanisms included self-esteem, body image, and friendship. Behavioral mechanisms included sleep quality, diet quality, and recreational screen time. Pearson correlations between physical activity measures and psychiatric symptoms were calculated, with false discovery rate correction applied to account for the number of tests performed. Mediation analyses were performed when a correlation (defined as false discovery rate P &lt; .05) between exposure and outcome was observed and were adjusted for confounders.ResultsAmong the 4216 children included in this study, the mean (SD) age was 6.0 (0.4) years at visit 1, and 2115 participants (50.2%) were girls. More sports participation was associated with fewer internalizing symptoms (β for direct effect, −0.025; SE, 0.078; P = .03) but not externalizing symptoms. Self-esteem mediated the association between sports participation and internalizing symptoms (β for indirect effect, −0.009; SE, 0.018; P = .002). No evidence was found for associations between any other neurobiological, psychosocial, or behavioral variables. No association was found between other types of physical activity and psychiatric symptoms at these ages.Conclusions and RelevanceThe integrated model presented in this cohort study evaluated potential mechanisms mediating associations between physical activity and psychiatric symptoms in youth. Self-esteem mediated an association between sports participation in childhood and internalizing symptoms in adolescence; other significant mediations were not observed. Further studies might explore whether larger effects are present in certain subgroups (eg, children at high risk of developing psychiatric symptoms), different ages, or structured sport-based physical activity interventions.

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Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

Cited by 181 publications

References 38 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

Genomics of Alzheimer Disease

Neurobiological, Psychosocial, and Behavioral Mechanisms Mediating Associations Between Physical Activity and Psychiatric Symptoms in Youth in the Netherlands

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