Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease (original) (raw)
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Neurobiology of Aging, 2016
The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-b (Ab) peptide deposition and amyloid burden (ε4 > ε3 > ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)emediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Ab levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Ab burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Ab and amyloid deposition. We further demonstrate that a widespread reduction of brain Ab burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.
Proceedings of the National Academy of Sciences, 1999
We quantified the amount of amyloid -peptide (A) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP V717F؉/؊ TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F؉/؊ Apoe ؊/؊ TG mice as old as 22 mo of age, whereas age-matched APP V717F ؉/؊ Apoe ؉/؊ and Apoe ؉/؉ TG mice display abundant amyloid deposition. The amount of A immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe ؉/؉ > Apoe ؉/؊ Ͼ Ͼ Apoe ؊/؊), and no A immunoreactivity was detected in the cerebral cortex of APP V717F؉/؊ Apoe ؊/؊ TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both A1-40 and A1-42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of A immunoreactive deposits and in virtually all thioflavine-Sfluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to A peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A, ultimately affecting clearance of protease-resistant A/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.
Human APOE Isoform-Dependent Effects on Brain -Amyloid Levels in PDAPP Transgenic Mice
Journal of Neuroscience, 2009
To investigate the role of human apolipoprotein E (apoE) on A deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and A peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain A and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain A deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of A42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain A burden, and the majority of apoE was associated with A. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 Ͻ E3 Ͻ Ͻ E2), resulting in early and dramatic apoE isoform-dependent effects on brain A levels (E4 Ͼ Ͼ E3 Ͼ E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.
Apolipoprotein E isoforms in Alzheimer's disease pathology and etiology
Microscopy Research and Technique, 2000
The apolipoprotein E (apoE) ⑀4 allele increases risk of Alzheimer's disease (AD), perhaps by accelerating plaque formation, or by impairing neuron repair. Considerable evidence supports both mechanisms. AD patients with ⑀4 have more and earlier amyloid deposits than do patients without ⑀4. The same is true of non-demented control subjects. In vitro, all apoE isoforms inhibit amyloid  protein (A) aggregation, but apoE4 less effectively than apoE3. Transgenic amyloid-producing mice expressing apoE3 or apoE4 develop less A deposition than apoE knockout mice. These observations are consistent with an effect of apoE isoforms on A aggregation in AD. ApoE is important for neurite maintenance since apoE knockout mice lose neurites and suffer behavioral deficits with aging or treatment with excitotoxins. ApoE4 mice show similar defects, but apoE3 mice are normal. AD patients with ⑀4 show more neuritic deficits than ⑀3 carriers. ApoE ⑀4 also worsens neurological impairment in head injury, stroke, and multiple sclerosis. Thus, apoE4 is less effective at neurite maintenance. Perhaps ⑀4 increases AD risk by both mechanisms: allowing amyloid deposition and failing to repair neurites. In either case, introducing apoE3 or apoE2 into the brain, for example by gene therapy or cell grafts, might delay AD progression.
Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade
International journal of Alzheimer's disease, 2012
The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or "pathological chaperone". Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of a...
Acta neuropathologica communications, 2015
Amyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aβ plaques and CAA in humans. Studies in mouse models that develop Aβ deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoE(m/4)). The 5XFAD/apoE(m/4) mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoE(m/m) and 5XFAD/apoE(4/4) mice. In 5XFAD/apoE(m/4) mice, we found that Aβ parenchym...
Proceedings of the National Academy of Sciences, 2000
Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (4 > 3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid- (A) peptide and its conversion to a fibrillar form. To determine the effect of apoE on A deposition and AD pathology, we compared APP V717F transgenic (TG) mice expressing mouse, human, or no apoE (apoE ؊͞؊ ). A severe, plaque-associated neuritic dystrophy developed in APP V717F TG mice expressing mouse or human apoE. Though significant levels of A deposition also occurred in APP V717F TG, apoE ؊͞؊ mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP V717F TG, apoE ؊͞؊ mice resulted in fibrillar A deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP V717F TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.