Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy - PubMed (original) (raw)

Review

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Chia-Chen Liu et al. Nat Rev Neurol. 2013 Feb.

Erratum in

Abstract

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

PubMed Disclaimer

Figures

Figure 1

Figure 1. APOE ε4 is a major genetic risk factor for Alzheimer disease

(a) The ApoE2, E3, and E4 isoforms, which are encoded by the ε2, ε3 and ε4 alleles of the APOE gene, respectively, differ from one another at amino acid residues 112 and/or 158 (red circles). ApoE has two structural domains: the N-terminal domain, which contains the receptor-binding region (residues 136–150), and the C-terminal domain, which contains the lipid-binding region (residues 244–272); the two domains are joined by a hinge region. A meta-analysis demonstrated a significant association between the ε4 allele of APOE and AD. (b) APOE ε4 increases the risk of AD and lowers the age of disease onset in a gene-dose-dependent manner., Abbreviations: AD, Alzheimer disease; ApoE, Apolipoprotein E.

Figure 2

Figure 2. Apolipoprotein E and amyloid-β metabolism in the brain

The main Aβ clearance pathways include receptor-mediated uptake by neurons and glia, drainage into interstitial fluid or through the BBB, and proteolytic degradation by IDE and neprilysin. Impaired clearance of Aβ can cause Aβ accumulation in brain parenchyma, leading to formation of neurotoxic Aβ oligomers and amyloid plaques. Aβ accumulation in the perivascular region leads to CAA, which disrupts blood vessel function. ApoE is primarily synthesized by astrocytes and microglia, and is lipidated by the ABCA1 transporter to form lipoprotein particles. Lipidated ApoE binds to soluble Aβ and facilitates Aβ uptake through cell surface receptors, including LRP1, LDLR, and HSPG, in a manner that probably depends on ApoE isoform and its level of lipidation. ApoE facilitates binding and internalization of soluble Aβ by glial cells, disrupts Aβ clearance at the BBB in an isoform-dependent manner (ApoE4 > ApoE3 > ApoE2) and influences CAA pathogenesis. Abbreviations: Aβ, amyloid-β; ABCA1, ATP-binding cassette A1; BBB, blood–brain barrier; CAA, cerebral amyloid angiopathy; HSPG, heparan sulphate proteoglycan; IDE, insulin-degrading enzyme; LDLR, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; LXR, liver X receptor.

Figure 3

Figure 3. The role of Apolipoprotein E4 in Alzheimer disease pathogenesis

ApoE4 confers toxic gain of function, loss of neuroprotective function or both in the pathogenesis of Alzheimer disease. Key functional differences between ApoE4 and ApoE3 are illustrated. Abbreviations: Aβ, amyloid-β; ApoE, Apolipoprotein E.

Figure 4

Figure 4. Abnormal brain function and enhanced neuropathology and memory decline in cognitively normal APOE ε4 carriers

(a) 18F-fluorodeoxyglucose PET images show that cognitively normal APOE ε4 carriers have lower glucose metabolism than do noncarriers. (b) APOE ε4 carriers exhibit a greater increase in functional MRI signal in brain regions associated with task performance, and show increases in additional regions compared with APOE ε3 carriers. (c) Age-related memory decline occurs more rapidly in APOE ε4 carriers than noncarriers, starting from age 55–60 years. (d) APOE ε4 carriers show increased cerebral Aβ deposition which persists in greater frequencies with age compared with noncarriers. Increased PiB binding and reduced CSF Aβ42 levels reflect cerebral amyloid deposition. Abbreviations: Aβ, amyloid-β; APOE, apolipoprotein E; CSF, cerebrospinal fluid; PiB, Pittsburg compund B. Part a, is modified, with permission from the National Academy of Science, USA © Small, G. W. et al. Proc. Natl Acad. Sci. USA 97, 6037–6042 (2000). Part b, is modified, with permission from the Massachusetts Medical Society © Bookheimer, S. Y. et al. N. Engl. J. Med. 343, 450–456 (2000). Part c, is modified, with permission from the Massachusetts Medical Society © Caselli et al. N. Engl. J. Med. 361, 255–263 (2009). Part d is modified, with permission, from John Wiley and Sons © Morris, J. C. et al. Ann. Neurol. 67, 122–131 (2010).

Similar articles

Cited by

References

    1. Alzheimer’s Association. 2012 Alzheimer’s disease facts and figures. Alzheimer’s dement. 2012;8:131–168. - PubMed
    1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. - PubMed
    1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387–403. - PubMed
    1. Roberson ED, et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316:750–754. - PubMed
    1. Zheng H, Koo E. Biology and pathophysiology of the amyloid precursor protein. Mol Neurodegener. 2011;6:27. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources