Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

Martiskainen, Henna; Haapasalo, Annakaisa; Kurkinen, Kaisa M.A.; Pihlajamäki, Jussi; Soininen, Hilkka; Hiltunen, Mikko

doi:10.1517/14728222.2013.789862

Cited by 40 publications

(25 citation statements)

References 127 publications

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“…A β 42 is the key neurotoxic and pro‐inflammatory component in AD,7, 8 but recent studies have also pointed toward a potential anti‐inflammatory role for A β 42 under certain conditions 13, 14. Since ApoE is the major mediator of A β clearance from the brain,44 we wanted to address potential changes in the plasma concentration of A β among different APOE groups. While plasma A β 40 and A β 42 levels remained unaffected between the different APOE groups , we observed a significant negative association between plasma A β 42 and hs‐CRP levels even after age adjustment, suggesting that A β 42 may confer protective effect(s) against peripheral inflammation.…”

Section: Discussionmentioning

confidence: 99%

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

Martiskainen

Takalo

Solomon

et al. 2018

Ann Clin Transl Neurol

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ObjectiveApolipoprotein E (APOE) ε4 allele is a well‐established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation‐related parameters in population‐based cohorts.MethodsAssociation of cardiovascular, metabolic, and inflammation‐related parameters with the APOE polymorphism in a large Finnish Metabolic Syndrome in Men (METSIM) cohort and Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER) were investigated. Brain‐specific effects were addressed in postmortem brain samples.ResultsIndividuals carrying the APOE ε4 allele displayed significantly elevated serum/plasma LDL cholesterol and apolipoprotein B levels. APOE ε3ε4 and ε4ε4 significantly associated with lower levels of plasma high‐sensitivity C‐reactive protein (hs‐CRP). Plasma amyloid‐β 42 (Aβ42) and reduced hs‐CRP levels showed an association independently of the APOE status.InterpretationThese data suggest that the APOE ε4 allele associates with lower levels of hs‐CRP in individuals without dementia. Moreover, Aβ42 may encompass anti‐inflammatory effects reflected by reduced hs‐CRP levels.

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Section: Discussionmentioning

confidence: 99%

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

Martiskainen

Takalo

Solomon

et al. 2018

Ann Clin Transl Neurol

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“…In brief, three major functions have been suggested for astrocyte-derived ApoE-containing lipoproteins: 1) the transfer of phospholipids and cholesterol via ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG1 15 ; 2) interaction with the LDL receptor superfamily of proteins located on the surface of neurons to facilitate axonal growth and neuronal survival 16 ; and 3) interaction with the LDL receptor-related protein 1 (LRP1)-dependent cellular uptake pathway, in the deposition of amyloid plaques 17,18 . Although there is minimal direct interaction between ApoE and soluble Aβ in CSF 19 , apoE isoforms in ApoE-containing lipoprotein complexes can regulate the metabolism of soluble Aβ bycompeting for the binding of LRP1 with Aβ in astrocytes 19,20 .…”

Section: Lipoprotein Synthesis Assembly and Metabolism In Astrocytesmentioning

confidence: 99%

What are lipoproteins doing in the brain?

Wang

Eckel

2014

Trends in Endocrinology & Metabolism

191

153

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Lipoproteins in plasma transport lipids between tissues, however, only high density lipoproteins (HDL) appear to traverse the blood brain barrier; thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes and are found on HDL. In the hippocampus and other brain regions lipoproteins help regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, i.e. through lipoprotein lipase (LPL) and the LDL receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance.

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“…Liu et al showed increased level of APOE in LDL-receptor knockout mice, which resulted in decrease of the cholesterol levels in the brain (Liu et al 2010b). Due to the involvement of the LDL receptors in the clearance of Aβ associated with BBB permeability, it was suggested that these modulating agents could be potentially considered for treatment of AD (Martiskainen et al 2013). …”

Section: Introductionmentioning

confidence: 99%

Cholesterol as a modifying agent of the neurovascular unit structure and function under physiological and pathological conditions

et al. 2017

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The brain, demanding constant level of cholesterol, precisely controls its synthesis and homeostasis. The brain cholesterol pool is almost completely separated from the rest of the body by the functional blood-brain barrier (BBB). Only a part of cholesterol pool can be exchanged with the blood circulation in the form of the oxysterol metabolites such, as 27-hydroxycholesterol (27-OHC) and 24S–hydroxycholesterol (24S–OHC). Not only neurons but also blood vessels and neuroglia, constituting neurovascular unit (NVU), are crucial for the brain cholesterol metabolism and undergo precise regulation by numerous modulators, metabolites and signal molecules. In physiological conditions maintaining the optimal cholesterol concentration is important for the energetic metabolism, composition of cell membranes and myelination. However, a growing body of evidence indicates the consequences of the cholesterol homeostasis dysregulation in several pathophysiological processes. There is a causal relationship between hypercholesterolemia and 1) development of type 2 diabetes due to long-term high-fat diet consumption, 2) significance of the oxidative stress consequences for cerebral amyloid angiopathy and neurodegenerative diseases, 3) insulin resistance on progression of the neurodegenerative brain diseases. In this review, we summarize the current state of knowledge concerning the cholesterol influence upon functioning of the NVU under physiological and pathological conditions.

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Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

Cited by 40 publications

References 127 publications

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

What are lipoproteins doing in the brain?

Cholesterol as a modifying agent of the neurovascular unit structure and function under physiological and pathological conditions

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