Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E epsilon4 allele

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.     

Effect of bilobalide B on cholinergic hippocampal neurons exposed to cholesterol and apolipoprotein E4*☆

BACKGROUND： Extracts of ginkgo biloba leaves have been reported to improve nerve function and activity in Alzheimer＇s disease, which is associated with reduced secretion of cholinergic neurotransmitter in hippocampal neurons. OBJECTIVE： To validate the protective effect of bilobalide B against in vitro injury of cholinergic neurons of the hippocampus induced by combined cholesterol and apoE4 DESIGN, TIME AND SETTING： This randomized, controlled animal experiment was performed in the Pathology Laboratory, Tianjin University of Traditional Chinese Medicine from July 2003 to July 2006. MATERIALS： Neonatal Wistar rats, 1-day-old, both male and female, and mean body mass of 5 g were selected for this study. Cholesterol and apolipoprotein E4 （apoE4） were purchased from Sigma Company （USA）, bilobalide B was purchased from Tianjin Zhongyi Pharmaceutical Factory, batch number 20050312. METHODS： Hippocampal neurons were divided into three groups： a normal control group （routinely added media）, a model group （exposed to media containing 40 mg/L cholesterol and 30 mg/L apoE4 for 24 hours） and a bilobalide B group （exposed to media containing 160 mg/L bilobalide B for 16 hours, and then with addition of 40 mg/L cholesterol and 30 mg/L apoE4 for an additional 24 hours）. MAIN OUTCOME MEASURES： Levels of acetylcholine （ACh） and activity of acetylcholinesterase （ACHE） and choline acetyltransferase （CHAT） in hippocampal neurons were determined by microdosage hydroxylamine colorimetry, hydroxylamine colorimetry and radiological chemistry, respectively. RESULTS： The ACh level was significantly lower in the model group than that in the normal control group （P 〈 0.01）, while it was markedly higher in the bilobalide B group than in the model group （P 〈 0.05）. Activity of AChE was significantly decreased in the model group compared with the normal control group （P 〈 0.05）. However, there was no significant difference between the model group and the bilobalide B group ?     

Effect of bilobalide B on cholinergic hippocampal neurons exposed to cholesterol and apolipoprotein E4

BACKGROUND: Extracts of ginkgo biloba leaves have been reported to improve nerve function and activ- ity in Alzheimer's disease, which is associated with reduced secretion of cholinergic neurotransmitter in hip- pocampal neurons. OBJECTIVE: To validate the protective effect of bilobalide B against in vitro injury of cholinergic neurons of the hippocampus induced by combined cholesterol and apoE4 DESIGN, TIME AND SETTING: This randomized, controlled animal experiment was performed in the Pathology Laboratory...     

Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment

BACKGROUND: Subjects with mild cognitive impairment (MCI) have been shown to have reduced hippocampal volumes relative to normal elderly control subjects. The presence of the apolipoprotein E epsilon4 (APOE*E4) allele has been associated with greater hippocampal atrophy in women than in men with Alzheimer disease. This relationship has not been demonstrated in MCI. OBJECTIVE: To examine the relationship between APOE genotype and hippocampal volume in men and women with MCI. DESIGN: This study evaluated MCI in 193 subjects (86 women and 107 men) participating in a multicenter clinical trial, all of whom underwent magnetic resonance imaging at their baseline visit. We evaluated the association among the number of APOE*E4 alleles, memory performance, and hippocampal volume in men and women with tests of means and multiple linear regressions. RESULTS: Compared with MCI subjects with no APOE*E4 alleles, women with 1 or 2 APOE*E4 alleles were found to have significantly reduced hippocampal volume, whereas men only showed a significant reduction in hippocampal volume when carrying 2 APOE*E4 alleles. Worsening of performance on a delayed word recall task (Alzheimer's Disease Assessment Scale cognitive subscale) showed an identical pattern in association with APOE*E4 allele dose and sex. Furthermore, when controlling for memory performance on delayed word recall, the APOE*E4 effect on hippocampal volumes was attenuated in men, but remained significant in women. CONCLUSION: The APOE*E4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women than in men.     

The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males

OBJECTIVE: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. METHODS: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE epsilon4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. RESULTS: The APOE epsilon4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE epsilon2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE epsilon4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE epsilon2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE epsilon2 nor APOE epsilon4 allele frequency varied significantly between any of the clinical subtypes. CONCLUSIONS: In FTLD not associated with mutations in tau gene, possession of APOE epsilon4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.     

The apolipoprotein E epsilon 4 allele increases the risk of drug-induced hallucinations in Parkinson's disease.

To determine whether the apolipoprotein E (APOE) epsilon 4 allele is a risk factor of drug-induced hallucinations in nondemented patients with Parkinson's disease (PD), the proportions of patients with hallucinations in groups with and without the APOE epsilon 4 allele were compared with a chi 2 test. The contribution of the APOE epsilon 4 allele to the occurrence of hallucinations was further evaluated by means of logistic regression models, adjusting for potential prognostic variables. Thirteen (76%) of the 17 patients who had the epsilon 4 allele had visual hallucinations, compared with 20 (23%) of the 88 patients without the epsilon 4 allele (p < 0.0001; odds ratio = 11.05; 95% CI 3.24-37.67). In addition, treatment with dopamine agonists also contributed to an increased risk of hallucinations (p = 0.0011). After adjustment for age, severity of parkinsonism, duration of treatment, dose of levodopa, and treatment with dopamine agonists, the association between the presence of the epsilon 4 allele and the occurrence of visual hallucinations remained significant (p = 0.0003). Nondemented PD patients with the APOE epsilon 4 allele have a high risk of developing drug-induced visual hallucinations. Further studies are needed to evaluate which proportion of these patients will end up developing dementia.     

Genetics of Alzheimer's disease: an insight into presenilins and apolipoprotein E instigated neurodegeneration

Alzheimer's disease (AD) has long been characterized primarily by extracellular deposition of Aβ protein. It is a genetically intricate neurodegenerative disorder. Presenilins (PSs) (presenilin 1 [ PS1] and presenilin 2 [PS2]) and apolipoprotein E (APOE) ε4 allele have been found to be potentially linked to Aβ accumulation and accrual in turn contributing for the AD pathology, despite their significant role in processing of amyloid precursor protein (APP) and lipid metabolism. In this review, the role of PSs and APOE in general physiology and AD pathology due to the mutations occurring in them has been discussed. In addition, a few animal models employed to study these mutations and a few therapeutic avenues studied were summarized.     

Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype

The epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for the development of AD. The authors compared longitudinal rates of change in hippocampal volume as a function of APOE genotype in nondemented elderly individuals. Rate of volumetric loss was significantly greater among epsilon4+ compared with epsilon4- individuals. These results indicate that individuals positive for the APOE epsilon4 allele may show a greater rate of hippocampal atrophy than their epsilon4- counterparts, even in the absence of a diagnosis of AD.     

Deficits in spatial learning and memory is associated with hippocampal volume loss in aged apolipoprotein E4 mice

Apolipoprotein E ε4 (ApoE4) has been implicated as a potential genetic risk factor for dementia. In this study, we investigate the effect of ApoE4 on learning and memory, changes in brain volume and neuroinflammatory responses in brain of ApoE4 transgenic mice. Four groups of male mice with ApoE4 and age-matched wild type (WT) (6-, 12-, 18- and 24-month) were studied. Spatial learning and retaining of mice was examined in the Morris Water Maze (MWM). Changes in brain volume (including the whole brain, hippocampus, cortex, total ventricles, and caudate putamen) were assessed by using 7T small animal MRI. Neuroinflammatory responses were analyzed by measuring the levels of microglia (Iba-1), iNOS, TNFα, and IL-6 quantitatively. In the MWM, ApoE4 mice showed longer escape latency (p < 0.05) and swim distance (p < 0.05) at age 12 month and older, comparing with the WT mice. They also demonstrated poor memory retention in the probe test (p < 0.05). Brain atrophy was significant in ApoE4 mice than age-matched WT mice (18 months: 0.079 ± 0.004 versus 0.086 ± 0.003, p = 0.018; and 24 months: 0.074 ± 0.005 versus 0.084 ± 0.006, p = 0.008). The expression of Iba-1, iNOS, and TNFα in hippocampus and cortex were significantly higher in ApoE4 mice than in WT mice at 12 months and older. These data suggest that ApoE4 plays an important role in learning and memory impairment. These deficits are associated with neuroinflammatory responses that may in turn lead to atrophy in hippocampus and cortex.     

Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women.

OBJECTIVE: To determine whether the presence of a single epsilon4 allele of the APOE gene is associated with an increased rate of hippocampal volume loss or decline in cognition in healthy women in their sixth decade of life. METHODS: Nine APOE-epsilon4 allele-negative (mean age +/- SD, 60.6 +/- 10.2 years) and 16 APOE-epsilon4 allele-positive (mean age +/- SD, 55.1 +/- 6.0 years) healthy women underwent neurocognitive testing and MRI at the time of entry into the study (baseline) and 2 years later. Neurocognitive testing consisted of the Buschke-Fuld Free Recall, verbal fluency tests, the Rey Figure Test, the Wechsler Memory Scale-Revised, and the Wechsler Adult Intelligence Survey-Revised Block Design. Hippocampal volume determinations were based on manual outlining of sagittal slices aided by axial, coronal, and three-dimensional views of high-resolution 124-slice whole-brain scans; the scans were obtained with a 1.5-tesla scanner using a T1-weighted three-dimensional gradient echo sequence with RF spoiling (TR/TE/flip angle, 24 msec/3 msec/30 degrees ). RESULTS: The percent change in hippocampal volume per year was greater in the APOE-epsilon4 allele-positive group (mean +/- SD, 2.32 +/- 1.75%) than in the APOE-epsilon4 allele-negative group (mean +/- SD, 0.77 +/- 1.02%; t = 2.41; p < 0.03, two-tailed test). There were no significant differences between the two groups in terms of any of the cognitive measures, and hippocampal volume loss was not correlated with changes in any of the above-mentioned cognitive measures. CONCLUSIONS: The presence of a single APOE-epsilon4 allele is associated with an increased rate of hippocampal volume loss in healthy women in their sixth decade of life that is not related to any detectable memory changes.     

Functional consequences of hippocampal neuronal ectopia in the apolipoprotein E receptor-2 knockout mouse

Little is known about the impact ectopically located neurons have on the functional connectivity of local circuits. The ApoER2 knockout mouse has subtle cytoarchitectural disruptions, altered prepulse inhibition, and memory abnormalities. We evaluated this mouse mutant as a model to study the role ectopic neurons play in the manifestation of symptoms associated with brain diseases. We found that ectopic CA1 pyramidal and inhibitory neurons in the ApoER2 knockout hippocampus are organized into two distinct stratum pyramidale layers. In vitro analyses found that ApoER2 is not required for neurons to reach maturity in regard to dendritic arborization and synaptic structure density, and electrophysiological testing determined that neurons in both strata pyramidale are integrated into the hippocampal network. However, the presence of these two layers alters the spatiotemporal pattern of hippocampal activity, which may explain why ApoER2 knockout mice have selective cognitive dysfunctions that are revealed only under challenging conditions.     

Associative recognition in mild cognitive impairment: Relationship to hippocampal volume and apolipoprotein E

Associative memory involves remembering relations between items of information and is critically dependent on the hippocampus, a brain structure that shows early changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. We examined associative and item memory in aMCI with a focus on the role of medial-temporal lobe regions and genetic risk for Alzheimer's disease. Twenty-four individuals with aMCI and 21 demographically matched healthy older adults underwent associative recognition testing, structural brain imaging, and apolipoprotein E (ApoE) genotyping. A significant interaction between group and recognition type indicated poorer associative recognition than item recognition across tasks in the aMCI group relative to controls. Within the aMCI group, associative but not item recognition showed sizable and significant correlations with hippocampal volume (but not with other medial temporal-lobe structures) and with number of ApoE ε4 alleles. Correlations were smaller and generally not significant in the control group. Our findings replicate and extend previous studies by showing an associative recognition impairment in aMCI that is not accounted for by an item recognition deficit, is related to structural integrity of the hippocampus, and increases with genetic risk for Alzheimer's disease.     

Effects of genistein on hippocampal neurodegeneration of ovariectomized rats

To investigate the mechanism underlying the neurodegeneration of postmenopausal women, the effect of genistein on hippocampal neurodegeneration was investigated in ovariectomized (OVX) Sprague-Dawley rats. Three-month-old female Sprague-Dawley rats were randomly divided into four groups: sham operated; OVX only; genistein-treated OVX (OVX-genistein); and estradiol benzoate-treated OVX (OVX-EB). Genistein and EB were subcutaneously injected into rats of the OVX-genistein and OVX-EB groups, respectively, once a day from the second day after surgery. Behavioral testing began on day 31 after surgery and lasted 5 d. The activities of superoxide dismutase and content of malondialdehyde in serum, the concentration of intrasynaptosome-free calcium, membrane relative viscosity of cerebral synaptosomes, and mean optical density (MOD) of the hippocampal synaptophysin immunoreactivity product were measured, respectively, in the eighth week after surgery. It was found that the escape latency in the OVX-EB and the OVX-genistein groups was significantly lower than that in the OVX control group (p<0.05), whereas in the behavioral test, the platform-passing number was higher than in the OVX control group (p<0.05). [Ca²⁺] _i in the cerebral cortical and hippocampal synaptosome of the OVX-only group was remarkably higher than that in the other three groups (p<0.01). The hippocampal synaptosome membrane viscosity of the OVX-only group was significantly higher than that in the sham-operated, OVX-EB (p<0.05) and the OVX-genistein (p<0.01) groups. The MOD of synaptophysin immunoreactive product in the radiation layers of CA1, CA2, CA3 and the molecular layer of the dentate gyrus of the OVX-only group was significantly lower than in the sham-operated, OVX-genistein, and OVX-EB groups (p<0.01). These results suggested that genistein, which has antioxidant properties similar to estradiol, could be used as a substitute for estradiol to prevent or treat central neurodegeneration in postmenopausal women.     

Differential effects of kainic-acid-induced hippocampal lesions on the acquisition of the jump-box avoidance task in mice

This research examined the effects of kainic-acid (KA)-induced hippocampal lesions on the acquisition of a jump-box avoidance task in mice. When the hippocampal lesion was unilateral, mice with lesions in the lateral portion of the CA1 region showed deficits in acquisition while those with lesions in the CA3 region and/or the medial portion of the CA1 region did not. When the hippocampal lesion was bilateral, on the other hand, mice with lesions in the CA3 region and/or the lateral portion of the CA1 region were deficient in acquisition while those with lesions in the medial portion of the CA1 region were not. Among the mice with various KA-induced hippocampal lesions avoidance responses were not correlated with the level of open field activity, indicating that acquisition differences observed are not dependent upon, nor secondary to, levels of spontaneous activity. These results strongly suggest that there exist regional differences in the involvement of hippocampal pyramidal cell layers in acquisition of the jump-box avoidance task: both the CA3 region and the lateral portion of the CA1 region are involved in acquisition, while the medial portion of the CA1 region is not.     

β-淀粉样蛋白和载脂蛋白E4降低神经元膜流动性

为了研究 Aβ和 Apo E对神经元膜流动性的影响 ,探索 Aβ和 Apo E的神经毒性机制 ,制备急性分离的新生 SD大鼠海马和皮质神经元细胞悬液 ,采用显微准弹性激光散射技术 ,分析单个神经元散射光强度的自相关函数 (ACF) ,通过公式由 ACF拟合出反映细胞膜流动性的频移线宽 Γ。结果发现 Aβ2 5～ 3 5和 Apo E4作用 5min和 3 5min后均降低海马和皮质神经元 ACF的衰减速率及频移线宽 Γ,而 Apo E3对两者无影响 ,提示 Aβ和 Apo E4均可降低神经元膜流动性。