Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β1–42 peptide in mice

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An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aβ1–42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aβ1–42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aβ1–42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aβ1–42 administration. Aged mice also responded to Aβ1–42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aβ1–42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aβ1–42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.HighlightsIndoleamine-2,3-dioxigenase mediates behavioural disturbances induced by Aβ1–42.Aging exacerbates Aβ1–42-induced cognitive and anxiety deficits.Aging aggravates Aβ1–42-mediated neuroinflammation.Aging aggravates BDNF and antioxidant deficiency elicited by Aβ1–42.Aging further increase KYN dysregulation in brain of Aβ1–42-treated mice.

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