The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease

doi:10.1016/S0165-0173(98)00008-3

Brain Research Reviews

Volume 27, Issue 2, July 1998, Pages 119-142

https://doi.org/10.1016/S0165-0173(98)00008-3 Get rights and content

Abstract

The importance of apolipoproteins in the central nervous system became increasingly clear with the association in 1993 of the ϵ4 allele of apolipoprotein E with familial and sporadic late-onset Alzheimer's disease. Apolipoprotein E is a ligand for several receptors, most of which are found to some extent in the brain. This review summarizes the various apolipoproteins and lipoprotein receptors found in the brain. A growing body of evidence now implicates irregular lipoprotein metabolism in several neurodegenerative disorders. We then focus on research linking apolipoprotein E and Alzheimer's disease, from clinical studies to biochemical models, which may explain some of the complex neurobiology of this disorder.

Introduction

The discovery of apolipoproteins and their receptors was due in large part to their role in plasma lipoprotein metabolism and cholesterol homeostasis. However, new functions for these proteins have been discovered, especially with regards to the nervous system. This review will focus on the role of apolipoproteins and their receptors in the central nervous system (CNS), with emphasis on apolipoprotein E (ApoE) in the neurodegenerative disorder Alzheimer's disease (AD). The pathways for receptor-mediated lipoprotein metabolism, cholesterol homeostasis and apoE structure–function relationships have been extensively studied and reviewed elsewhere. For a review of the low-density-lipoprotein (LDL) receptor pathway, see Brown and Goldstein [30]; for a review of the role of apoE in the redistribution of cholesterol among cells and tissues, see Mahley [147]; for a review of apoE structure–function relationships, see Weisgraber [282].

Section snippets

(Apo)lipoproteins in the central nervous system

Cholesterol and other lipids are used for membrane synthesis and for many other anabolic or catabolic activities by cells throughout the body including those of the CNS, a site of high lipid turnover 6, 33, 229. Although cells composing the nervous tissue are capable of de novo synthesis of lipid molecules, they can also bind and take-up lipoproteins made available in the local environment for their lipid requirements 202, 209. Since the blood–brain barrier presumably prevents the passage of

Lipoprotein receptors of the central nervous system

In addition to the LRP, several other receptors for lipoproteins were shown to be expressed in the mammalian brain including the LDLR, the very low density lipoprotein receptor (VLDLR), gp330/megalin, and the recently described apolipoprotein E receptor 2 (apoER2) [121]. All of these receptors are members of a single family of proteins that share structural and functional similarities. They all bind and internalize apoE-containing lipoproteins, although LRP and gp330 possess several other

Neuronal plasticity in the peripheral nervous system

Initial work demonstrating a neuronal function for apoE dates back to 1986. At that time, models were characterized, in which a role for apoE was proposed for the coordinated storage and redistribution of cholesterol among cells of injured and regenerating peripheral nerves 100, 256. Following sciatic nerve crush in the rat, macrophage-secreted apoE levels increased 100- to 200-fold compared to controls [100]. ApoE synthesis peaked after about one week and slowly returned to baseline levels by

Polymorphic nature of human ApoE

An important biochemical characteristic of human apoE stems from a genetic polymorphism, first established by Utermann et al. [277]using isoelectric focusing. Polymorphisms within the human apoE gene (located on chromosome 19) account for the three major apoE isoforms, designated apoE2, apoE3 and apoE4, arising from respective alleles ϵ2, ϵ3 and ϵ4. The result of this polymorphism is three homozygous genotypes (ϵ2/ϵ2, ϵ3/ϵ3, and ϵ4/ϵ4) and three heterozygous genotypes (ϵ2/ϵ3, ϵ2/ϵ4, and ϵ3/ϵ4).

ApoE isoforms on neurite outgrowth

Peripheral nerves normally contain low levels of apoE, however dramatic increases in the levels of apoE occur following denervating crush injury (see above)25, 28, 100, 133, 256. In vitro experiments using PC12 cells (a pheochromocytoma cell line) further demonstrated that apoE-containing lipoproteins obtained from regenerating nerves are internalized by a receptor mediated mechanism [101]. In mixed cultures from fetal dorsal root ganglion cultures, incubation with β-very low density

ApoE-deficient mice

Due to the key role of apoE in lipid transport and the pathology of atherosclerosis, apoE-deficient or knockout mice were created [206]. These mice have recently been used for investigations into the potential importance of apoE in the nervous system. Popko et al. [216]and Goodrum et al. [73]demonstrated that peripheral nerve regeneration following sciatic nerve crush occurred equally as well in apoE deficient mice compared to control animals. These results indicated that nerve repair and

ApoE as a risk factor

Using nonparametric linkage analysis methods, genetic markers from chromosome 19 (where both the genes for apoE and the LDL receptor are located), suggested linkage to late-onset familial AD [197]. It was then demonstrated that the frequency of the ϵ4 allele of apoE was increased in late-onset familial AD when compared to age-matched controls [267]. This result was quickly confirmed in sporadic AD patients, which account for approximately 95% of all late-onset AD cases [210]. This result has

Senile plaques

One of the characteristic neuropathological features of AD is the presence of amyloid-containing senile plaques (SP). SPs comprise aggregates of beta-amyloid (Aβ) protein, which is derived from APP, the amyloid precursor protein. The role of Aβ in the pathogenesis AD is strongly supported by findings that associate specific point mutations in APP with families having autosomal dominant early-onset familial AD 34, 69. The first report to link apoE to amyloid plaques was by Namba et al. [175]in

ApoE, cholinergic dysfunction and treatment in Alzheimer's disease

The role of apoE in the CNS is particularly important in relation to the function of the cholinergic system, which relies heavily on lipid availability to synthesize acetylcholine (ACh) in neurons (Fig. 2). Brain membrane phospholipids, particularly phosphatidylcholine (PC) and phosphatidylethanolamine (PE), have been shown to serve as donor intermediates for choline, a rate-limiting precursor of ACh [23]. The release from PC of free choline precursor for ACh synthesis is accomplished in a

ApoE ϵ4 gene dose as a risk factor for other central nervous system pathologies

Since the many neuropathological features of AD are not exclusive to this disease, many studies have been performed examining the extent of apoE allele distribution in other CNS pathologies. Dementia associated with cortical Lewy bodies is the second most common form of amyloid-forming degenerative dementia in the elderly after AD [81]. A genetic association of the ϵ4 allele of apoE has now been reported with most Lewy body-related disorders, including senile dementia of the Lewy body type 15,

Other potential risk factors related to lipoprotein metabolism in Alzheimer's disease

Although apoE4 has been postulated to be involved in neurofibrillary tangles and plaque formation, its exact role in AD remains to be established. The fact that approximately one-third to one-half of late-onset AD patients do not carry the ϵ4 allele indicates that other risk factors must be involved in the pathogenic process. One hypothesis involves defects in uptake of cellular lipoproteins leading to lipid metabolism dysfunction in these subjects. Poor cholesterol and phosphatidylcholine

Acknowledgements

The authors received funding from the Fonds de la Recherche en Santé du Québec (FRSQ), the Medical Research Council of Canada (MRCC) and the Alzheimer Society of Canada to JP. UB is a recipient of a studentship from the Fonds pour la Formation de Chercheurs et l'Aide à la Recherche (FCAR) and from the Alzheimer Society of Montreal. MD is a recipient of a fellowship from the FRSQ. PK is a recipient of a fellowships from Specia/FNG and INSERM/FRSQ CR is a recipient of a fellowship from the IPSEN

References (301)

R Adroer et al.
Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases
Neurosci. Lett.
(1995)
A al-Chalabi et al.
Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease
Lancet
(1996)
P Alaupovic
Apolipoprotein composition as the basis for classifying plasma lipoproteins. Characterization of ApoA- and ApoB-containing lipoprotein families
Prog. Lipid Res.
(1991)
P Amouyel et al.
The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt–Jakob disease. The French Research Group on Epidemiology of Human Spongiform Encephalopathies
Lancet
(1994)
M Andersson et al.
Age-dependent modifications in the metabolism of mevalonate pathway lipids in rat brain
Mech. Ageing Dev.
(1995)
D Avramopoulos et al.
Apolipoprotein E allele distribution in parents of Down's syndrome children
Lancet
(1996)
H Basun et al.
Apolipoprotein epsilon-4 allele and disease progression in patients with late-onset Alzheimer's disease
Neurosci. Lett.
(1995)
S Bellosta et al.
Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produce differential effects on neurite outgrowth
J. Biol. Chem.
(1995)
R Benjamin et al.
Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease
Neurodegeneration
(1995)
C Berr et al.
Apolipoprotein E allele epsilon-4 is linked to increased deposition of the amyloid beta-peptide (A-beta) in cases with or without Alzheimer's disease
Neurosci. Lett.
(1994)

P Bertrand et al.

Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer's disease

Mol. Brain Res.

(1995)

D.H Bessesen et al.

Spinal cord of the rat contains more lipoprotein lipase than other brain regions

J. Lipid Res.

(1993)

I Borghini et al.

Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid

Biochim. Biophys. Acta

(1995)

J.K Boyles et al.

Accumulation of apolipoproteins in the regenerating and remyelinating mammalian peripheral nerve. Identification of apolipoprotein D, apolipoprotein A-IV, apolipoprotein E, and apolipoprotein A-I

J. Biol. Chem.

(1990)

J.K Boyles et al.

Identification, characterization, and tissue distribution of apolipoprotein D in the rat

J. Lipid Res.

(1990)

C Brandes et al.

Avian and murine LR8B and human apolipoprotein E receptor 2: differentially spliced products from corresponding genes

Genomics

(1997)

G Bu et al.

Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons

J. Biol. Chem.

(1994)

S Datta et al.

Structure and expression of dog apolipoprotein C-II and C-III mRNAs. Implications for the evolution and functional constraints of apolipoprotein structure

J. Biol. Chem.

(1987)

J.R Day et al.

Purification and molecular cloning of human apolipoprotein F

Biochem. Biophys. Res. Commun.

(1994)

H.V de Silva et al.

A 70-kDa apolipoprotein designated ApoJ is a marker for subclasses of human plasma high density lipoproteins

J. Biol. Chem.

(1990)

D Drayna et al.

Cloning and expression of human apolipoprotein D cDNA

J. Biol. Chem.

(1986)

R Egensperger et al.

The apolipoprotein E epsilon 4 allele in Parkinson's disease with Alzheimer lesions

Biochem. Biophys. Res. Commun.

(1996)

N.A Elshourbagy et al.

The nucleotide and derived amino acid sequence of human apolipoprotein A-IV mRNA and the close linkage of its gene to the genes of apolipoproteins A-I and C-III

J. Biol. Chem.

(1986)

A.M Fagan et al.

Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein

J. Biol. Chem.

(1996)

B Gao et al.

Sequence of a cDNA encoding bovine apolipoprotein H

Gene

(1993)

I Gordon et al.

Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice

Neurosci. Lett.

(1995)

S.H Han et al.

Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer's disease and in age-matched controls

Exp. Neurol.

(1994)

G.E Handelmann et al.

Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro

J. Lipid Res.

(1992)

L.A Hansen et al.

Apolipoprotein-E ϵ4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer's disease

Neurosci. Lett.

(1994)

J Hardy et al.

ApoE genotype and Down's syndrome

Lancet

(1994)

J Hardy et al.

Senile dementia of the Lewy body type has an apolipoprotein epsilon-4 allele frequency intermediate between controls and Alzheimer's disease

Neurosci. Lett.

(1994)

D Ibarreta et al.

Apolipoprotein E genotype in Spanish patients of Alzheimer's or Parkinson's disease

J. Neurol. Sci.

(1995)

R Anderson et al.

Absence of central cholinergic deficits in apoE knockout mice

Psychopharmacology

(1997)

A Anouti et al.

Normal distribution of apolipoprotein E alleles in progressive supranuclear palsy

Neurology

(1996)

T Arendt et al.

Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein ϵ4 allele

J. Neurosci.

(1997)

U Beffert et al.

β-amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons

J. Neurochem.

(1998)

U Beffert et al.

Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer's disease

Ann. NY Acad. Sci.

(1996)

M.D Bell et al.

Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS

J. Neurocyt.

(1994)

R Benjamin et al.

Apolipoprotein E genes in Lewy body and Parkinson's disease

Lancet

(1994)

C Betard et al.

Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia

Neuroreport

(1994)

K Blennow et al.

Cerebrospinal fluid apolipoprotein E is reduced in Alzheimer's disease

Neuroreport

(1994)

R Blesa et al.

High apolipoprotein E epsilon 4 allele frequency in age-related memory decline

Ann. Neurol.

(1996)

J.K Blusztajn et al.

Phosphatidylcholine as a precursor of choline for acetylcholine synthesis

J. Neural Trans.

(1987)

J.K Boyles et al.

Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system

J. Clin. Invest.

(1985)

J.K Boyles et al.

A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve

J. Clin. Invest.

(1989)

M.S Brown et al.

A receptor-mediated pathway for cholesterol homeostasis

Science

(1986)

G Bu et al.

39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein

EMBO J.

(1995)

R.M. Burton, H.C., Agrawal, The turnover of protein and lipid components of myelin membranes, in: R.M. Burton, L....

M.C Chartier-Harlin et al.

Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene

Nature

(1991)

M.C Chartier-Harlin et al.

Apolipoprotein E, ϵ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region

Hum. Mol. Genet.

(1994)

Cited by (167)

Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory
2015, Neurobiology of Learning and Memory
Mutations in Amyloid β Precursor Protein (APP) and in genes that regulate APP processing – such as PSEN1/2 and ITM2b/BRI2 – cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDD_KI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDD_KI/ApoE3, ApoE4, FDD_KI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16–17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16–17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3-carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers.
Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer's disease
2014, Neurobiology of Aging
The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1–42 concentrations without significant modifications of lipid hydroperoxide levels.
Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in high density lipoprotein biogenesis and remodeling at the blood-brain barrier
2014, Journal of Biological Chemistry
Phospholipid transfer protein (PLTP) is a key protein involved in biogenesis and remodeling of plasma HDL. Several neuroprotective properties have been ascribed to HDL. We reported earlier that liver X receptor (LXR) activation promotes cellular cholesterol efflux and formation of HDL-like particles in an established in vitro model of the blood-brain barrier (BBB) consisting of primary porcine brain capillary endothelial cells (pBCEC). Here, we report PLTP synthesis, regulation, and its key role in HDL metabolism at the BBB. We demonstrate that PLTP is highly expressed and secreted by pBCEC. In a polarized in vitro model mimicking the BBB, pBCEC secreted phospholipid-transfer active PLTP preferentially to the basolateral (“brain parenchymal”) compartment. PLTP expression levels and phospholipid transfer activity were enhanced (up to 2.5-fold) by LXR activation using 24(S)-hydroxycholesterol (a cerebral cholesterol metabolite) or TO901317 (a synthetic LXR agonist). TO901317 administration elevated PLTP activity in BCEC from C57/BL6 mice. Preincubation of HDL₃ with human plasma-derived active PLTP resulted in the formation of smaller and larger HDL particles and enhanced the capacity of the generated HDL particles to remove cholesterol from pBCEC by up to 3-fold. Pre-β-HDL, detected by two-dimensional crossed immunoelectrophoresis, was generated from HDL₃ in pBCEC-derived supernatants, and their generation was markedly enhanced (1.9-fold) upon LXR activation. Furthermore, RNA interference-mediated PLTP silencing (up to 75%) reduced both apoA-I-dependent (67%) and HDL₃-dependent (30%) cholesterol efflux from pBCEC. Based on these findings, we propose that PLTP is actively involved in lipid transfer, cholesterol efflux, HDL genesis, and remodeling at the BBB.
Liver X receptors: Emerging therapeutic targets for Alzheimer's disease
2013, Pharmacological Research
Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathological accumulation of ß-amyloid peptides (Aß) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiological and biochemical data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Aß, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRß) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathology through multiple pathways. Reports indicate that genetic loss of either lxra or lxrß in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Aß production with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biology of LXRs, with an emphasis on their probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.
Genetic mouse models of neurodegenerative diseases
2011, Progress in Molecular Biology and Translational Science
Neurodegenerative diseases are generally characterized by the selective degeneration of particular neuronal populations and the accumulation of abnormal or aggregated proteins within, but occasionally external to, neurons in affected brain regions. These diseases can be broadly classified as disorders of cognition and memory or movement, and both features can often coexist in a single disease. In recent years, the identification of genetic mutations that cause rare monogenic familial disease has revolutionized our understanding of the molecular basis of neurodegenerative disease and has provided new targets for the development of disease-modifying therapies. An essential part of this process has been the development of genetic animal models that accurately recapitulate the essential features of each disease, with particular emphasis on the use of mouse models. Such mouse models have provided unique insight into the molecular mechanism(s) through which genetic mutations precipitate neurodegeneration and produce associated clinical and pathological phenotypes. In this review, we provide an overview of the current status, uses and limitations of genetic mouse models for understanding major neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis.
The Antifungal Antibiotic Filipin as a Diagnostic Tool of Cholesterol Alterations in Lysosomal Storage Diseases and Neurodegenerative Disorders
2023, Antibiotics

View all citing articles on Scopus

View full text

Full-length reviewThe neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease

Abstract

Introduction

Section snippets

(Apo)lipoproteins in the central nervous system

Lipoprotein receptors of the central nervous system

Neuronal plasticity in the peripheral nervous system

Polymorphic nature of human ApoE

ApoE isoforms on neurite outgrowth

ApoE-deficient mice

ApoE as a risk factor

Senile plaques

ApoE, cholinergic dysfunction and treatment in Alzheimer's disease

ApoE ϵ4 gene dose as a risk factor for other central nervous system pathologies

Other potential risk factors related to lipoprotein metabolism in Alzheimer's disease

Acknowledgements

Neurosci. Lett.

Lancet

Prog. Lipid Res.

Lancet

Mech. Ageing Dev.

Lancet

Neurosci. Lett.

J. Biol. Chem.

Neurodegeneration

Neurosci. Lett.

Mol. Brain Res.

J. Lipid Res.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Lipid Res.

Genomics

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Gene

Neurosci. Lett.

Exp. Neurol.

J. Lipid Res.

Neurosci. Lett.

Lancet

Neurosci. Lett.

J. Neurol. Sci.

Absence of central cholinergic deficits in apoE knockout mice

Psychopharmacology

Normal distribution of apolipoprotein E alleles in progressive supranuclear palsy

Neurology

Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein ϵ4 allele

J. Neurosci.

β-amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons

J. Neurochem.

Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer's disease

Ann. NY Acad. Sci.

Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS

J. Neurocyt.

Apolipoprotein E genes in Lewy body and Parkinson's disease

Lancet

Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia

Neuroreport

Cerebrospinal fluid apolipoprotein E is reduced in Alzheimer's disease

Neuroreport

High apolipoprotein E epsilon 4 allele frequency in age-related memory decline

Ann. Neurol.

Phosphatidylcholine as a precursor of choline for acetylcholine synthesis

J. Neural Trans.

Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system

J. Clin. Invest.

A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve

J. Clin. Invest.

A receptor-mediated pathway for cholesterol homeostasis

Science

39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein

EMBO J.

Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene

Nature

Full-length review
The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease