Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

Sutcliffe, J. Gregor; Hedlund, Peter B.; Thomas, Elizabeth A.; Bloom, Floyd E.; Hilbush, Brian S.

doi:10.1002/jnr.22603

Cited by 104 publications

(79 citation statements)

References 29 publications

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“…Recently it was reported that subchronic administration of imatinib in mice can reduce A␤ levels in plasma and that this decrease in peripheral A␤ was sufficient to reduce A␤ levels in the brain (28). Contrary to these findings, we found subchronic administration of imatinib in rats had no effect on the level of A␤40 in plasma despite achieving a plasma exposure in excess of the cellular IC 50 .…”

Section: Discussioncontrasting

confidence: 99%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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Background: ␥-Secretase activating protein, GSAP, was identified as a novel regulator of ␥-secretase and amyloid-␤ production. Results: Reducing GSAP expression in cells decreased amyloid-␤ generation. However, overexpression of GSAP in cells and recombinant GSAP in vitro did not modulate amyloid-␤ generation. Conclusion:The relationship between GSAP and ␥-secretase is unclear. Significance: GSAP is not a validated therapeutic target for Alzheimer disease.

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Section: Discussioncontrasting

confidence: 99%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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“…Peptides in general poorly cross the BBB (49,50), but can be transported into the brain if specific transporters and/or receptors with a transport function are expressed in brain endothelium either under physiological (51,52) or pathological conditions, as in the case of RAGE and Aβ transport (43). Recent studies have independently confirmed earlier observations that circulating Aβ is an important precursor for brain Aβ (7,10,33) by demonstrating that peripheral Aβ can accelerate cerebral β-amyloidosis in a mouse model (11) and that liver serves as an important source of brain Aβ (53). These recent findings have extended earlier work showing that circulating Aβ enters the brain via RAGEmediated transport across the BBB, either as a soluble molecule (10) and/or via Aβ-laden monocytes (33), and contributes to the formation of parenchymal amyloid plaques, as shown, for example, in nonhuman primates (54).…”

Section: Discussionmentioning

confidence: 80%

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

Deane¹,

Singh²,

Sagare³

et al. 2012

J. Clin. Invest.

524

446

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In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40-and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APP sw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APP sw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

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“…Perhaps the most widely studied aspect of BBB with regards to AD, is its role in the clearance and sequestration of amyloid beta to the peripheral circulation (28,(67)(68)(69). Interestingly, individuals with high serum fibrinogen have been shown at greater risk of AD (70,71).…”

Section: Page 17 Of 22mentioning

confidence: 99%

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Hay¹,

Johnson²,

Young³

et al. 2015

J Neuropathol Exp Neurol

115

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Traumatic brain injury (TBI) is a risk factor for dementia, with studies describing a mixed neurodegenerative pathology in late survivors. However, the mechanisms driving this post-TBI neurodegeneration remain elusive. Increasingly, blood brain barrier (BBB) disruption is recognized in a range of neurological disorders, including dementias; although little is known of the consequences of TBI on the BBB. From the Glasgow TBI Archive autopsy cases of single, moderate or severe TBI (n=70) were selected to include a range of survivals from acute (10h to 13days) to long-term (1 to 47years) survival, together with age-matched, uninjured controls (n=21). Multiple brain regions were examined for fibrinogen (FBG) and immunoglobulin G (IgG) immunohistochemistry. Following TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multi-focal, abnormal, perivascular and parenchymal FBG and IgG immunostaining localized to grey matter, with preferential distribution towards the crests of gyri and deep neocortical layers. In contrast, where present, controls showed only limited, localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.

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Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

Cited by 104 publications

References 29 publications

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

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