Effect of High Cholesterol Regulation of LRP1 and RAGE on Aβ Transport Across the Blood-Brain Barrier in Alzheimer’s Disease

Zhou, Rui; Chen, Lili; Hai, Yang; Li, Ling; Liu, Juan; Chen, Le; Hong, Wenjuan; Wang, Congguo; Ma, Jingjing; Huang, Jie; Zhou, Xin‐Fu; Liu, Dong; Zhou, Hua‐Dong

doi:10.2174/1567205018666210906092940

Cited by 24 publications

(13 citation statements)

References 78 publications

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“…Accordingly, PCSK9 inhibition was shown to reduce neuronal apoptosis [ 54 ]. On the other hand, the cholesterol depletion hypothesis is in full accordance with the results of in vivo animal studies, in which silencing of lipoprotein receptors, implicated in cholesterol uptake and target of PCSK9, led to cognitive impairment [ 55 , 56 , 57 , 58 , 59 ], which was likely related to neuronal loss. Notably, as reported by Oliveira J. et al, the cognitive impairment observed in LDLr −/− mice was associated with neuronal apoptosis in brain regions related to memory formation [ 58 ].…”

Section: Discussionsupporting

confidence: 80%

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

Papotti

Adorni

Marchi

et al. 2022

IJMS

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The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer’s disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.

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Section: Discussionsupporting

confidence: 80%

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

Papotti

Adorni

Marchi

et al. 2022

IJMS

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“…(low-density lipoprotein receptor-related protein 1)Low-density lipoprotein receptor-related protein 1 is required for survival of oligodendrocyte progenitor cells (OPC) (Schäfer et al, 2019). Since cholesterol can down-regulate LRP1 (Zhou et al, 2021), this could potentially impair function of OPCs and impair myelin repair. OPCs require LRP1 to maintain normal cholesterol and require LRP1 to differentiate into mature oligodendrocytes (OLs) (Lin et al, 2017).…”

Section: Lrp1mentioning

confidence: 99%

“…Low-density lipoprotein receptor-related protein 1 is the main transporter for Abeta out of cells and out of brain via the BBB (Shibata et al, 2000;Zlokovic et al, 2010). Hypercholesterolemia decreased LRP1 expression, which would decrease Abeta efflux across the BBB, and increased RAGE expression, which would increase Abeta influx through the BBB, in cerebral endothelial cells (Zhou et al, 2021). Hypercholesterolemia increased brain apoptosis in AD mice.…”

Section: Cholesterol Effects On Abeta Transportersmentioning

confidence: 99%

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Sharp

DeCarli

Jin

et al. 2023

Front. Aging Neurosci.

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We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

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“…LRP1 plays a vital role in the pathological process of AD. The BBB plays an important role in the mechanism of transporting clearance of Aβ in AD, and LRP1 is a key receptor for the BBB to transport Aβ, and one of its functions in the brain endothelium is to transport Aβ from brain tissue to blood circulation, thus playing a role in clearing Aβ in the brain (Zhou et al., 2021 ). Moreover, the recently reports suggested that TSIIA was able to improve protein expression of glucose transporter 1 (GLUT1) and LRP1, thereby improving pathological progression in AD mice (Ma et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease

et al. 2022

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The blood–brain barrier (BBB) is a protective barrier for brain safety, but it is also a major obstacle to the delivery of drugs to the cerebral parenchyma such as the hippocampus, hindering the treatment of central nervous system diseases such as Alzheimer’s disease (AD). In this work, an anti-AD brain-targeted nanodrug delivery system by co-loading icariin (ICA) and tanshinone IIA (TSIIA) into Aniopep-2-modified long-circulating (Ang2-ICA/TSIIA) liposomes was developed. Low-density lipoprotein receptor-related protein-1 (LRP1) was a receptor overexpressed on the BBB. Angiopep-2, a specific ligand of LRP1, exhibited a high binding efficiency with LRP1. Additionally, ICA and TSIIA, drugs with neuroprotective effects are loaded into the liposomes, so that the liposomes not only have an effective BBB penetration effect, but also have a potential anti-AD effect. The prepared Ang2-ICA/TSIIA liposomes appeared narrow dispersity and good stability with a diameter of 110 nm, and a round morphology. Cell uptake observations, BBB models in vitro , and imaging analysis in vivo showed that Ang2-ICA/TSIIA liposomes not only penetrate the BBB through endocytosis, but also accumulate in N2a cells or brain tissue. The pharmacodynamic analysis in vivo demonstrated that Ang2-ICA/TSIIA liposomes could improve AD-like pathological features in APP/PS1 mice, including inhibiting neuroinflammation and oxidative stress, reducing apoptosis, protecting neurons, and improving cognitive function. Therefore, Ang2-ICA/TSIIA liposomes are considered a potentially effective therapeutic strategy for AD.

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Effect of High Cholesterol Regulation of LRP1 and RAGE on Aβ Transport Across the Blood-Brain Barrier in Alzheimer’s Disease

Cited by 24 publications

References 78 publications

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease

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