Amyloid Efflux Transporter Expression at the Blood-Brain Barrier Declines in Normal Aging

Abstract

Reduced clearance of amyloid β peptides (Aβ) across the blood-brain barrier contributes to amyloid accumulation in Alzheimer disease. Amyloid β efflux transport is via the endothelial low-density lipoprotein receptor-related protein 1 (LRP-1) and P-glycoprotein (P-gp), whereas Aβ influx transport is via the receptor for advanced glycation end products. Because age is the major risk factor for developing Alzheimer disease, we measured LRP-1 and P-gp expression and associated transporter expression with Aβ accumulation in aging rats. Quantitative LRP-1 and P-gp microvessel expression was measured by immunohistochemistry (IHC); LRP-1 and P-gp expression were assessed in microvessel isolates by Western blotting. There was an age-dependent loss of capillary LRP-1 across all ages (3-36 months) by IHC (linear trend p = 0.0004) and between 3 and 20 months by Western blotting (linear trend p < 0.0001). There was a late (30-36 months) P-gp expression loss by IHC (p < 0.05) and Western blotting (p = 0.0112). Loss of LRP-1 correlated with Aβ42 accumulation (p = 0.0121) and very nearly with Aβ40 (p = 0.0599) across all ages. Expression of LRP-1 correlated negatively with the expression of receptor for advanced glycation end products (p < 0.0004). These data indicate that alterations in LRP-1 and P-gp expression seem to contribute progressively to Aβ accumulation in aging.

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…It was found in different mice models and human tissue, that ABCB1 expression is decreased in patients with capillary CAA (capCAA), a disease characterized by Aβ-deposits in the cerebral capillaries (Carrano et al, 2014). The decline of the levels of the transporter at the BBB occurs during normal aging, and is positively correlated with the accumulation of Aβ (Silverberg et al, 2010). Due the contribution of ABC transporters on Aβ clearance in AD, they have been proposed as potential therapeutic targets (Krohn et al, 2011).…”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…Ezáltal igazolódott e transzporterek szerepe az amiloid plakkok lerakódásának regulálásában. Több tanulmány igazolta a vér-agy gát endothelsejtjeinek apicalis felszínén a P-gp-expresszió szignifikáns csökkenését a természetes öregedési folyamattal párhuzamosan [55][56][57][58][59]. Mindezen megfigyelések alapján megfontolandó stratégia a P-gp-expresszió fokozása, illetve a transzporter aktiválása az időskori Alzheimer-kór megelőzésében.…”

The ABCB1 Transporter in Alzheimer’s Disease

“…Decreased clearance of amyloid-β from the brain may lead to elevated amyloid-β levels. There is an age-related decrease in P-gp expression, Aβ 1-42 itself downregulates the expression of P-gp and other Aβ transporters, which could exacerbate the intracerebral accumulation of Aβ and thereby accelerate neurodegeneration in AD and cerebral β-amyloid angiopathy [11]. Amyloid efflux transporter expression at the BBB declines with aging in normal conditions [14], and expression of P-gp protein is significantly lower in hippocampal vessels of patients with AD compared to normal individuals [12].…”

“…One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation [5][6][7][8][9][10][11][12]. Deficiency of either of the two major efflux pumps, ABCB1 and ABCG2, involved in Aβ trafficking across the BBB, results in increased accumulation of peripherallyinjected Aβ in the brain [13].…”

“…ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the BBB and brain parenchyma, affect Aβ transport (flux) across the BBB contributing to the pathogenesis of Alzheimer's disease (AD) [5][6][7][8][9][10][11][12]. One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters.…”