The ageing systemic milieu negatively regulates neurogenesis and cognitive function

Villeda, Saul; Luo, Jian; Mosher, Kira Irving; Zou, Bende; Britschgi, Markus; Bieri, Gregor; Stan, Trisha; Fainberg, Nina; Ding, Zhaoqing; Eggel, Alexander; Lucin, Kurt M.; Czirr, Eva; Park, Jeong‐Soo; Couillard‐Després, Sébastien; Aigner, Ludwig; Li, Ge; Peskind, Elaine R.; Kaye, Jeffrey; Quinn, Joseph F.; Galasko, Douglas; Xie, Xinmin; Rando, Thomas A.; Wyss‐Coray, Tony

doi:10.1038/nature10357

Cited by 1,528 publications

(1,698 citation statements)

References 32 publications

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“…Whether levels of these anti-ageing molecules are reduced in patients with AD, and whether they are pathophysiologically relevant to this disease, remain unknown. However, identification of these protective components could be of importance in understanding the pathogenesis of AD and in developing systemic rejuvenation therapies [68][69][70][71] .…”

Section: Blood Abnormalitiesmentioning

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 Abnormalitiesmentioning

confidence: 99%

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

et al. 2017

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“…For many of these chemokine proteins, there are reports that aging affect both their gene expression and protein levels (Mo et al., 2003; Whiting et al., 2015; Yung & Mo, 2003). One of these proteins, CCL11 or eotaxin has been proposed as an important factor in neurogenesis in parabiotic models of aging in mice models (Villeda et al., 2011). Our study provides supportive evidence that these class of proteins change with age in healthy older adults.…”

Section: Discussionmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

404

396

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To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

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“…Young and old peripheral nerves secrete CCL11 in the context of regeneration, but levels are already chronically elevated in old peripheral nerves independent of injury. Elevated CCL11 serum levels are detected in mice and humans of old age, negatively regulating neurogenesis in the CNS (Villeda et al, 2011) and interfering with nervous system functions. We demonstrated that CCL11 directly interferes with Schwann cell myelination in vitro (Figure 6) and in vivo (Figure 7)—suggesting it as an important component of the dysregulated inflammatory nerve microenvironment impairing peripheral nerve remyelination in old age; a notion supported by age‐dependent increases in CCR5 expression (Supporting information Figure S3C), a CCL11 receptor reported to be expressed by Schwann cells and upregulated upon peripheral nerve injury (Kiguchi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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The ageing systemic milieu negatively regulates neurogenesis and cognitive function

Cited by 1,528 publications

References 32 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

Plasma proteomic signature of age in healthy humans

Inflammaging impairs peripheral nerve maintenance and regeneration

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