Abstract
Amyloid-β (Aβ) is the main constituent of amyloid deposits in Alzheimer’s disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and Aβ deposition in AβPP-mice and double-transgenic mice with brain expression of AβPP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 µg LPS or vehicle, and were sacrificed 1.5 months thereafter. Aβ in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total Aβ deposition and increased Tween-soluble Aβ. This was associated with a reduced CXCL1, IL-1β, TNF-α-level and microgliosis, which correlated with amyloid deposition and total Aβ. In contrast, LPS did not change Aβ accumulation or inflammation marker in the double-transgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers Aβ-clearance in AβPP-transgenic mouse brain. The effects depend on HS and heparanase.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia
We found a ≈30% lower Congo red amyloid burden (p = 0.014) and a ≈50% lower Resorufin cerebral amyloid angiopathy (CAA)-burden (p = 0.011) in tgHpaSwe compared to tgSwe treated with phosphate-buffered saline (PBS)-vehicle (Fig. 1C,D), similar to previous findings[7]
We have previously reported that single-transgenic heparanase-overexpressing mice showed a reduced neuroinflammatory LPS-response when compared to non-transgenic mice[21]
Summary
Alzheimer’s disease (AD) is the most common form of dementia. It is a progressive neurodegenerative disease affecting multiple cognitive functions. We previously demonstrated a reduced acute neuroinflammatory response of heparanase-overexpressing mice after lipopolysaccharide (LPS)-stimulation. This was accompanied by an impaired clearance of aggregated Aβ when injected into the brain[21]. LPS is a strong inducer of inflammation and an efficient tool to study effects of neuroinflammation on Aβ-burden in amyloid-β precursor protein (AβPP)-transgenic mice. Our data demonstrated a favorable effect of a single pro-inflammatory stimulus on Aβ-clearance in the tgSwe mice. This was confirmed by lack of effect in tgHpaSwe with heparanase overexpression and consistent with microglial TLR4-signalling being involved
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