Imatinib methanesulfonate reduces hippocampal amyloid-beta and restores cognitive function following repeated endotoxin exposure

Weintraub, Marielle Kahn; Bisson, Courtney M.; Nouri, Jessica N.; Vinson, Benjamin T.; Eimerbrink, M.J.; Kranjac, Dinko; Boehm, Gary W.; Chumley, Michael J.

doi:10.1016/j.bbi.2013.05.002

Cited by 35 publications

(17 citation statements)

References 20 publications

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“…Consistent evidence has demonstrated that this protein is directly involved in the production and subsequent deposition of Aβ peptides in vitro and in vivo 20. GSAP is a key molecule responsible for the rate-limiting step in Aβ production by directly interacting with the γ-secretase complex, and for this reason it is an emerging potential new player in molecular and cellular mechanisms of relevance to AD brain amyloidosis2122.…”

Section: Discussionmentioning

confidence: 96%

Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Chu

Hoffman

et al. 2015

Sci Rep

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The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer’s disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 96%

Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Chu

Hoffman

et al. 2015

Sci Rep

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“…Considerable in vitro, animal model, and clinical data show that peripheral inflammations and infections are sufficient to increase brain amyloid load possibly by: augmenting amyloid beta synthesis (Weintraub, et al, 2013), disrupting the brain blood barrier and/or amyloid beta trafficking (Erickson, et al, 2012). Further clinical evidence for the importance of inflammation in brain amyloid accumulation is suggested by data coming from the Alzheimer’s Disease Neuroimaging Initiative.…”

Section: Discussionmentioning

confidence: 99%

Periodontal disease associates with higher brain amyloid load in normal elderly

Kamer¹,

Pirraglia²,

Tsui³

et al. 2015

Neurobiology of Aging

202

150

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Background The accumulation of amyloid β plaques (Aβ) is a central feature of Alzheimer’s disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory/infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Methods Thirty-eight cognitively normal, healthy, community residing elderly (mean age 61; 68% female) were examined in an Alzheimer’s Disease research center and a University-based Dental School. Linear regression models (adjusted for age, ApoE and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-PIB PET imaging. Results After adjusting for confounders, clinical attachment loss (≥ 3mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased 11C-PIB uptake in Aβ vulnerable brain regions (p=0.002). Conclusion We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with prior animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations.

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“…Finally, it remains unclear whether increased peripheral concentrations of Aβ result in its accumulation in the brain, with consequent neurodegeneration (Aβ hypothesis). Various animal studies have shown that peripheral infection and inflammation are sufficient to increase accumulation of Aβ in the brain, possibly due to passage of the peptide through the blood–brain barrier 37 . Kamer et al, 17 using positron emission tomography, found greater Aβ accumulation in the brain of cognitively healthy patients with versus without periodontal disease.…”

Section: Discussionmentioning

confidence: 99%

Association Between Periodontitis and Amyloid β Peptide in Elderly People With and Without Cognitive Impairment

Gil-Montoya¹,

Barrios²,

Santana³

et al. 2017

Journal of Periodontology

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Imatinib methanesulfonate reduces hippocampal amyloid-beta and restores cognitive function following repeated endotoxin exposure

Cited by 35 publications

References 20 publications

Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Periodontal disease associates with higher brain amyloid load in normal elderly

Association Between Periodontitis and Amyloid β Peptide in Elderly People With and Without Cognitive Impairment

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