Lipopolysaccharide alters the blood–brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) brains are characterized by accumulation of amyloid-ß protein (Aβ) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Aß accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Aß. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Aβ, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Aß, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Aß influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brainto-blood transporter of Aß, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Aß. Thus, inflammation potentially increases brain levels of Aß by three mechanisms: increased influx, decreased efflux, and increased neuronal production.

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…98,196 In a mouse lacking the antioxidant vitamin E, LRP-1-dependent brain efflux and systemic clearance of Ab are impaired. 197 Both LRP-1 and Pgp are functionally downregulated in the BBB in mice with systemic inflammation induced by LPS, 66,198 and this corresponds with impaired Ab efflux. 66,198 In contrast to AD, decreased function of these transporters after LPS was not attributed to reduced protein levels or oxidative damage.…”

“…197 Both LRP-1 and Pgp are functionally downregulated in the BBB in mice with systemic inflammation induced by LPS, 66,198 and this corresponds with impaired Ab efflux. 66,198 In contrast to AD, decreased function of these transporters after LPS was not attributed to reduced protein levels or oxidative damage. 66 Despite this, the antioxidant N-acetylcysteine (Nac) was found to protect against LPS-induced Ab efflux impairment and LRP-1 dysfunction, but not Pgp dysfunction in the BBB.…”

“…The BBB endothelial cells respond to inflammatory stimuli such as cytokines, 186 LPS,187,188 Ab,[189][190][191] and a truncated tau fragment 192 by activating signaling pathways that result in the upregulation of proinflammatory second messengers and reactive oxygen/ nitrogen species, ultimately causing BBB disruption and paracrine activation of surrounding cells that are responsive to such stimuli, 66,198 and this corresponds with impaired Ab efflux. 66,198 In contrast to AD, decreased function of these transporters after LPS was not attributed to reduced protein levels or oxidative damage. 66 Despite this, the antioxidant N-acetylcysteine (Nac) was found to protect against LPS-induced Ab efflux impairment and LRP-1 dysfunction, but not Pgp dysfunction in the BBB.…”

Alzheimer’s disease and gut microbiota

“…LPS may play a role in A accumulation and AD progression. Intraperitoneal injections of LPS to mice alters the BBB transport of A protein through increasing blood-to-brain influx, decreasing brain-to-blood efflux and increasing neuronal A production (Jaeger et al, 2009). Other studies showed that intraperitoneal injections of LPS to mice could also lead to serious memory problems (Kahn et al, 2012;Lee et al, 2008).…”

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

“…In particular, imaging (25) and animal modelling (23,26) studies in AD suggest BBB dysfunction is an early event in the course of disease and may contribute to its pathogenesis, perhaps as a result of impaired amyloid-² clearance or associated neuroinflammation (23,(27)(28)(29)(30)(31). Furthermore, neuropathology studies report complex vascular changes associated with BBB dysfunction in AD (32)(33)(34), with evidence of a correlation between histological evidence of BBB leakage and Alzheimer-type pathologies in 'normal' ageing (35).…”