Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease

Abstract

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the 4 allele increasing and the 2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-␤ peptide (A␤) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal A␤ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal A␤ 1-42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal A␤ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain A␤ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain A␤ burden and the subsequent development of neuritic plaques.amyloid plaques ͉ gene therapy A lzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of cognitive function and is associated with a characteristic neuropathology, including amyloid plaques, neurofibrillary tangles, synaptic loss, and neurodegeneration. Mutations in several genes, including the presenilins 1 and 2 and the amyloid precursor protein (APP) gene, have been shown to cause rare autosomal dominant forms of AD (1-3). Moreover, mutations of these genes have been shown to alter normal processing of APP to the 4-kDa amyloid-␤ peptide(s) (A␤), A␤ 1-40 or A␤ . AD mutations either increase production or alter the ratio of these peptides, which accumulate in the extracellular space to form amyloid-containing neuritic plaques. The apolipoprotein E (apoE) gene is a major risk factor for late-onset AD with the 4 allele increasing and the 2 allele decreasing the morbid risk for developing AD (4). Individuals carrying one or two 4 alleles develop AD at a younger age and have higher amyloid-plaque burden compared with individuals carrying two 3 alleles (5-8). In fact, several studies have demonstrated higher brain A␤ burden in elderly nondemented individuals carrying one or two 4 alleles, suggesting that apoE4 somehow contributes to A␤ deposition and brain amyloid burden (9, 10). Genetic epidemiological studies also suggest a protective role for the 2 allele, which in some studies has been shown to reduce the risk of AD by Ϸ50% (11).ApoE is a 34-kDa lipid-binding protein produced primarily in the liver, which functions in the transport of triglycerides and cholesterol (12). ApoE is also abundantly expressed in the brain, primarily in astrocytes and microglia, where it has been postulated to play a role in neuronal plasticity and synaptogenesis (13-17). How apoE contributes to AD pathogenesis is, however, as yet unclear. We and others have shown that apoE facilitates A␤ fibrillogenesis and deposition in vitro and in vivo and͞or participates in the clearance and degradation of A␤ in brain (18)(19)(20)(21)(22)(23).In the present study, we investigated whethe...

Degeneración macular asociada a la edad: asociación con el alelo épsilon4 del gen de la apolipoproteína E

“…The result of this study is opposite to that of the majority of studies which demonstrated the protecting role of allele ε4 in AMD (7)(8)(9)(10)(11)(12)(13)(14). Therefore, the reasons why this allele is a risk factor for cardiovascular diseases and Alzhei-mer (EA) (1,17,19) and not for AMD is an enigma, considering moreover that it has some histopathological similarities with EA (1). In summary, our study proves a non-protecting association of allele ε4 with AMD.…”

“…We have no explanation for the association found between allele _4 and an earlier expression of AMD in women. Estrogens could be related to this difference, because it is known they interact with APOE at the level of the brain and are involved in the synthesis of the beta-amyloid peptid by microglya (17,18 Clinical studies have provided contradictory results for the association between AMD and different APOE gen alleles (12)(13)(14)(15). The result of this study is opposite to that of the majority of studies which demonstrated the protecting role of allele ε4 in AMD (7)(8)(9)(10)(11)(12)(13)(14).…”

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

“…There is increasing evidence that MMPs, such as MMP-9, play important roles in regulating extracellular A␤ levels in brain , and our data demonstrating that apoE isoforms differentially determine the level of MMP-9 secretion from macrophages suggests that the reported effects of various apoE isoforms on amyloid deposition in vivo (Holtzman et al, 1999(Holtzman et al, , 2000Fagan et al, 2002;DeMattos et al, 2004;Dodart et al, 2005) may be due in part to differences in MMP-9 activity or secretion from apoE-expressing cells, including astrocytes, microglia, or macrophages. However, additional yet to be determined mechanisms may underlie the ability of macrophages to robustly degrade A␤ either in vitro or in vivo.…”

Diabetes mellitus en pacientes con enfermedad de Alzheimer: descripción clínica y correlación con el genotipo APOE en una muestra de población del departamento de Antioquia, Colombia

“…Other characteristics include synaptic dysfunction (5), decreased cerebral blood flow to the posterior portion of the left cingulate cortex (6), and cerebral endothelial dysfunction (7). Combinations of these and a variety of other factors may lead to neurodegeneration (8). Clinically, AD is defined by the presence of multiple cognitive alterations--characteristically amnesia and one or more of the following disturbances: aphasia, apraxia, agnosia, and alterations of normal executive functioning with progressive neurologic decline (9).…”

“…DM2 and the APOE4 allele have been found to be associated with an increased amount of amyloid plaques in the hippocampus, increased amount of NFT and increased cerebral amyloid angiopathy (8,29,30). ApoE is a circulating lipoprotein, which, by binding the low density lipoprotein (LDL) receptor, promotes the intracellular metabolism of lipids (31)(32)(33).…”