Accumulation Of Abeta In Brain Research Articles

Alzheimer disease β-amyloid activity mimics cholesterol oxidase

The abnormal accumulation of amyloid beta-peptide (Abeta) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Abeta binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol. Here we show that Abeta:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease. Abeta toxicity in neuronal cultures correlated with this activity, which was inhibited by Cu2+ chelators including clioquinol. Cell death induced by staurosporine or H2O2 did not elevate 4-cholesten-3-one levels. Brain tissue from AD subjects had 98% more 4-cholesten-3-one than tissue from age-matched control subjects. We observed a similar increase in the brains of Tg2576 transgenic mice compared with nontransgenic littermates; the increase was inhibited by in vivo treatment with clioquinol, which suggests that brain Abeta accumulation elevates 4-cholesten-3-one levels in AD. Cu2+-mediated oxidation of cholesterol may be a pathogenic mechanism common to atherosclerosis and AD.

Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor

Cerebrovascular deposition of amyloid beta-protein (Abeta) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Abeta cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Abeta in vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Abeta precursor protein (AbetaPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AbetaPP only in the brain, but at levels below those of endogenous mouse AbetaPP. Despite the paucity of human AbetaPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Abeta in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Abeta deposits that markedly increased with age. The vascular Abeta accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age. In vivo transport studies demonstrated that Dutch/Iowa mutant Abeta was more readily retained in the brain compared with wild-type Abeta. These results with Tg-SwDI mice demonstrate that overexpression of human AbetaPP is not required for early-onset and robust accumulation of both vascular and parenchymal Abeta in mouse brain.

Cholesterol, copper, and accumulation of thioflavine S-reactive Alzheimer's-like amyloid beta in rabbit brain.

Accumulation of beta-amyloid (Abeta) in the Alzheimer's disease (AD) brain is considered to be causally related to the behavioral symptoms of the disorder. Transgenic mouse models of AD exhibit accumulation of Abeta in the brain and simultaneous memory deficits, and Abeta accumulation is enhanced if dietary cholesterol is administered. Likewise, dietary cholesterol induces neuronal accumulation of Abeta in New Zealand white rabbits. The cholesterol-induced accumulation of Abeta in rabbit brain is increased when distilled drinking water is supplemented with 0.12 ppm copper ion (as copper sulfate) compared to the cholesterol-induced accumulation of Abeta in rabbit brain of animals given unaltered distilled water. The numbers of affected neurons and the intensity of neuronal Abeta immunoreactivity is consistently increased among animals administered the copper ion in their drinking water. A copper-induced decrease in the clearance of overproduced Abeta from the brain is proposed as the mechanism causing Abeta accumulation and resulting in the observed memory deficits. Current studies reveal that intensely immunoreactive neurons, extracellular deposits of Abeta, and brain vessels in cholesterol-fed rabbits given copper-supplemented water were stained by thioflavine S. Thioflavine S-reactive features were not observed in cholesterol-fed rabbits given unaltered distilled drinking water. The data suggest that there is an accumulation of fibrillar Abeta induced in the brains of rabbits fed a cholesterol diet and administered trace levels of copper ion in their drinking water.

Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol.

Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.

Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain.

Increased circulating cholesterol is known to promote risk of coronary artery disease. It is now emerging that cholesterol promotes production and accumulation of amyloid beta (Abeta) deposited in the hallmark pathologic lesion of Alzheimer's disease (AD), the senile plaque, perhaps by shifting away from normal metabolism of amyloid beta protein precursor (AbetaPP) to beta. Previous studies employing the cholesterol-fed rabbit model of AD demonstrated that induction of AD-like Abeta accumulation in brain could be reversed by co-administration of cholesterol lowering drugs or removing cholesterol, prompted initiation of an AD Cholesterol-Lowering (Statin) Treatment Trial. We now present data that identify a previously unrecognized role for dietary water quality on the severity of neuropathology induced by elevated cholesterol. Neuronal accumulation of Abeta induced by increased circulating concentrations of cholesterol in the New Zealand white rabbit is attenuated when distilled drinking water is administered compared to use of tap water. The numbers of neurons in cholesterol-fed rabbits that exhibited Abeta immunoreactivity, relative to normal chow-fed controls, increased approximately 2.5 fold among animals on tap water but only approximately 1.9 fold among animals on distilled water. This yielded a statistically significant approximately 28% reduction due to the use of distilled water. In addition, the subjectively assessed intensity of neuronal Abeta immunoreactivity was consistently reduced among cholesterol-fed rabbits allowed distilled drinking water compared to cholesterol-fed rabbits on tap water. As intensity of antibody immunoreactivity is likely related to concentration of antigen, the identified difference among cholesterol-fed rabbits allowed distilled drinking water may hold greater importance than a significant reduction in numbers of affected neurons. The effect on neuronal Abeta immunoreactivity intensity was observable among cholesterol-fed rabbits reared and allowed tap water when performing studies in three distinct locales. Pilot data suggest the possibility of increased clearance of Abeta from the brain, identified as increased blood levels, among cholesterol-fed rabbits administered distilled water compared to animals on tap water. The agent(s) occurring in tap water, excluded by distillation, promoting accumulation of neuronal Abeta immunoreactivity is(are) yet undisclosed, but arsenic, manganese, aluminum, zinc, mercury, iron and nitrate have tentatively been excluded because they were not identifiable (below detection limits) in the tap water of the three locales where the cholesterol-induced neuropathologic difference was observable. These findings suggest that water quality may impact on human health in the setting of increased circulating cholesterol levels, and could illustrate a truly simple life-style change that could be of benefit in AD.

Repetitive Mild Brain Trauma Accelerates Aβ Deposition, Lipid Peroxidation, and Cognitive Impairment in a Transgenic Mouse Model of Alzheimer Amyloidosis

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain Abeta deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased Abeta deposition as well as levels of Abeta and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Abeta accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.

Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.

Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid beta-amyloid (Abeta) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Abeta accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17beta-estradiol reduce the generation of Abeta by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.