Β-amyloid Plaques In Brain Research Articles

Effect and mechanism of traditional Chinese herbs against Aβ expression in brain tissues of mice with Alzheimer's disease

Objective: To investigate the effects of gastrodin, astragaloside and paeoniflorin from three types of traditional Chinese herbs against on β-amyloid plaques and memory ability in 5XFAD Alzheimer's disease (AD) transgenic mice. Methods: Seventy 5XFAD mice were randomly divided into seven groups, namely gastrodin-high and gastrodin-low dose groups (GAS-H, GAS-L), astragaloside-high and astragaloside-low dose groups (AST-H, AST-L), and paeoniflorin-high and paeoniflorin-low dose groups (PAE-H, PAE-L), and positive control group. Negative control groups were also established. After being treated for four months, 5XFAD mice were evaluated for memory ability and Aβ plaques, and the mechanism were was explored by utilizing cell model (over-expression Aβ and β-secretase). Results: Gastrodin, astragaloside and paeoniflorin enhanced the learning and memory ability of 5XFAD mice, and reduced Aβ in the cerebral homogenate and Aβ plaques in brain. Compared with the untreated transgenic positive group, Aβ plaques was reduced in hippocampus and cortex in the GAS-H group by 70.1% and 81.0%, in the AST-H group by 62.4% and 69.6%, and in the PAE-H group by 57.6% and 66.6% (P<0.01), respectively. Aβ was reduced in the cerebral homogenate of all groups. The effects were dose-dependent. In vitro study suggested a dose-dependent effect of gastrodin, astragaloside and paeoniflorin in reducing Aβ in cell models. Gastrodin suppressed BACE mRNA level by 32.9% (P<0.01), and suppressed β-secretase protein level by 47.9% (P<0.01). Conclusions: Three types of Chinese herbs can inhibit β-amyloid plaques in brain of AD. Gastrodin reduced Aβ production and accumulation by inhibiting β-secretase. Astragaloside and paeoniflorin have no demonstrable effects against β-secretase.

Fluorine-18 Radiolabeled Heterocycles as PET Tracers for Imaging &amp;#946; - Amyloid Plaques in Alzheimer’s Disease

Alzheimer's disease (AD), the most common form of dementia, is a progressive and fatal neurodegenerative disorder. The neuropathological hallmarks of AD generally revealed on postmortem brain tissue are the extracellular neuritic plaque deposits and intracellular neurofibrillary tangles. Significant evidence supports the pivotal role of β-amyloid peptides in the pathogenesis of AD. Therefore, The ability to image β-amyloid plaques in brain with noninvasive techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) may not only aid in presymptomatic identification of AD patients and differential diagnosis of patients with dementia, but also monitoring the effectiveness of anti-amyloid therapeutic strategies. For these reasons, development of β-amyloid plaque-specific imaging agents has been extensively pursued and reported. This review summarizes the current status of (18)F-labeled radioligand development for PET imaging of β-amyloid plaques. [(18)F]FDDNP is the first PET radioligand that demonstrated differential uptake and retention in the brain of AD patients, while a low signal-to-noise ratio in PET studies was indicated. At this time, [(18)F]3'-F-PIB (flutemetamol), [(18)F]AV-1 (florbetaben), [(18)F]AZD4694, and [(18)F]MK-3328 are undergoing phase II and III clinical trial. [(18)F]AV-45 (florbetapir) has recently been approved by FDA for use in patients being evaluated for Alzheimer's disease and other causes of cognitive decline. Several other (18)F-labeled radioligands based upon imidazo[1,2-a]pyridine, benzothiazole, stilbene, benzofuran, and benzoxazole core structures have also been synthesized and evaluated.

Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice.

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in brains of Alzheimer’s disease (AD) patients. Recent AD therapeutic interest has been directed toward a group of anti-amyloidogenic compounds extracted from plants. We orally administered the brain penetrant, small molecule phenolic compound ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated behavioral impairment and AD-like pathology. Oral FA treatment for 6 months reversed transgene-associated behavioral deficits including defective: hyperactivity, object recognition, and spatial working and reference memory, but did not alter wild-type mouse behavior. Furthermore, brain parenchymal and cerebral vascular β-amyloid deposits as well as abundance of various Aβ species including oligomers were decreased in FA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, reduced β-site APP cleaving enzyme 1 protein stability and activity, attenuated neuroinflammation, and stabilized oxidative stress. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a β-secretase modulator with therapeutic potential against AD.

Novel Cyclopentadienyl Tricarbonyl Complexes of 99mTc Mimicking Chalcone as Potential Single-Photon Emission Computed Tomography Imaging Probes for β-Amyloid Plaques in Brain

Rhenium and technetium-99m cyclopentadienyl tricarbonyl complexes mimicking the chalcone structure were prepared. These complexes were proved to have affinity to β-amyloid (Aβ) in fluorescent staining on brain sections of Alzheimer's Disease (AD) patient and binding assay using Aβ(1-42) aggregates, with K(i) values ranging from 899 to 108 nM as the extension of conjugated π system. In vitro autoradiograpy on sections of transgenic mouse brain confirmed the affinity of [(99m)Tc]5 (K(i) = 108 nM). In biodistribution, all compounds showed good initial uptakes into the brain and fast blood clearance, while the decreasing of initial brain uptakes correspond to increasing of conjugation length, from 4.10 ± 0.38% ID/g ([(99m)Tc]3) to 1.11 ± 0.34% ID/g ([(99m)Tc]5). These small technetium-99m complexes (<500 Da) designed by an integrated approach provide encouraging evidence that development of a promising (99m)Tc-labeled agent for imaging Aβ plaques in the brain may be feasible.

Synthesis and biological evaluation of novel technetium-99m labeled phenylbenzoxazole derivatives as potential imaging probes for β-amyloid plaques in brain

Two uncharged 99mTc-labeled phenylbenzoxazole derivatives were biologically evaluated as potential imaging probes for β-amyloid plaques. The 99mTc and corresponding rhenium complexes were synthesized by coupling monoamine–monoamide dithiol (MAMA) and bis(aminoethanethiol) (BAT) chelating ligand via a pentyloxy spacer to phenylbenzoxazole. The fluorescent rhenium complexes 6 and 9 selectively stainined the β-amyloid plaques on the sections of transgenic mouse, and showed high affinity for Aβ(1–42) aggregates (Ki=11.1nM and 14.3nM, respectively). Autoradiography in vitro indicated that [99mTc]6 clearly labeled β-amyloid plaques on the sections of transgenic mouse. Biodistribution experiments in normal mice revealed that [99mTc]6 displayed moderate initial brain uptake (0.81% ID/g at 2min), and quickly washed out from the brain (0.25% ID/g at 60min). The preliminary results indicate that the properties of [99mTc]6 are promising, although additional refinements are needed to improve the ability to cross the blood–brain barrier.

BODIPY-Based Molecular Probe for Imaging of Cerebral β-Amyloid Plaques

We designed and synthesized a BODIPY-based probe (BAP-1) for the imaging of β-amyloid plaques in the brain. In binding experiments in vitro, BAP-1 showed excellent affinity for synthetic Aβ aggregates. β-Amyloid plaques in Tg2576 mouse brain were clearly visualized with BAP-1. In addition, the labeling of β-amyloid plaques was demonstrated in vivo in Tg2576 mice. These results suggest BAP-1 to be a useful fluorescent probe for the optical imaging of cerebral β-amyloid plaques in patients with Alzheimer's disease.

Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.

Novel 18F-Labeled Benzofuran Derivatives with Improved Properties for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques in Alzheimer’s Brains

In vivo imaging of β-amyloid plaques in the brain may lead to the early diagnosis of Alzheimer's disease (AD) and monitoring of the progression and effectiveness of treatment. In the present study, we report on the development of two potential PET probes, [(18)F]FPYBF-2 ([(18)F]10) and [(18)F]FPHBF-2 ([(18)F]21), for imaging of β-amyloid plaques in AD brain. In experiments in vitro, 10 and 21 displayed high affinity for Aβ(1-42) aggregates (K(i) = 2.41 and 3.85 nM, respectively). In biodistribution experiments using normal mice, they displayed high uptake in the brain (7.38 and 8.18% ID/g at 2 min postinjection, respectively), and the radioactivity washed out from the brain rapidly (3.15 and 3.87% ID/g at 60 min postinjection, respectively), which is highly desirable for β-amyloid imaging agents. In vivo, they clearly labeled β-amyloid plaques in Tg2576 mice. Furthermore, the specific labeling of β-amyloid plaques by 10 and 21 was observed in autoradiographs of sections of autopsied AD brain. These new fluorinated benzofuran derivatives are promising PET probes for imaging cerebral β-amyloid plaques.

Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains.

A series of fluorinated benzofuran derivatives as potential tracers for positron emission tomography (PET) targeting β-amyloid plaques in the brains of patients with Alzheimer's disease (AD) were synthesized and evaluated. The derivatives were produced using an intramolecular Wittig reaction. In experiments in vitro, all displayed high affinity for Aβ(1-42) aggregates with K i values in the nanomolar range. Radiofluorinated 17, [(18)F]17, in particular labeled β-amyloid plaques in sections of Tg2576 mouse brain and displayed high uptake (5.66% ID/g) at 10 min postinjection, sufficient for PET imaging. In addition, in vivo β-amyloid plaque labeling can be clearly demonstrated with [(18)F]17 in Tg2576 mice. In conclusion, [(18)F]17 may be useful for detecting β-amyloid plaques in patients with AD.

Low Retention of [S-methyl-11C]MeS-IMPY to β-amyloid Plaques in Patients with Alzheimers Disease

Alzheimers disease (AD) is characterized pathologically by the accumulation of β-amyloid plaques in brain. We developed a novel positron emission tomographic (PET) radioligand, [11C]MeS-IMPY ([S-methyl-11C]N,N-dimethyl- 4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline). The objective of this study was to determine if [11C]MeS-IMPY can detect β-amyloid plaques in patients with AD. Ten subjects (4 patients with AD and 6 healthy controls) had PET scans of 90 min as well as serial sampling of arterial plasma. Total distribution volume was calculated from radioactivity in brain and concentrations of radioligand in arterial plasma. After injection of [11C]MeS-IMPY in both groups, peak brain uptake was high (∼ 450% SUV), peaked early at ∼ 2 min and washed out quickly. The time-course of brain radioactivity in all regions was virtually identical in AD patients and healthy controls. Although distribution volume of neocortical regions was ∼ 26% higher in AD patients than in controls, the differences were statistically insignificant (P = 0.143). In addition, distribution volume in all regions and in both groups increased during the entire scan, which is consistent with the accumulation of radiometabolite(s) in brain. The rapid washout of [11C]MeS-IMPY from brain may have been caused by inadequate binding affinity, and the small differences between patients and healthy subjects were likely caused, in part, by the accumulation of radiometabolite(s) in brain. We conclude that [11C]MeS-IMPY is able to image β-amyloid in brains of patients with AD, but that chemical analogs with higher affinity and non-problematic radiometabolites will be more useful imaging agents.

Development of Positron-Emission Tomography/Single-Photon Emission Computed Tomography Imaging Probes for in Vivo Detection of .BETA.-Amyloid Plaques in Alzheimer's Brains

Currently, the development of radiotracers for in vivo imaging of beta-amyloid plaques in Alzheimer's disease (AD) brains is an important, active area of molecular imaging. Postmortem brains of AD patients reveal neuropathologic features: the presence of beta-amyloid plaques and neurofibrillary tangles, which contain beta-amyloid peptides and highly phosphorylated tau proteins. Increases in the concentration of beta-amyloid in the course of the disease lead to changes in AD brains. Thus, when used in combination with positron-emission tomography/single-photon emission computed tomography (PET/SPECT), beta-amyloid imaging agents could serve as surrogate markers for the early diagnosis and neuropathogenetic studies of AD. Furthermore, quantitative evaluation of beta-amyloid plaques in the brain could facilitate the evaluation of the efficacy of antiamyloid therapies that are currently being investigated. This paper reviews our research on the development of PET/SPECT imaging agents for in vivo detection of beta-amyloid plaques in Alzheimer's brains.

Reduction of β-amyloid plaques in brain of transgenic mouse model of Alzheimer’s disease by EFRH-phage immunization

Antibodies to the epitope EFRH, representing residues 3–6 within the β-amyloid (Aβ) sequence, were previously shown to affect the solubility and disaggregation of Aβ fibrils in vitro. Here, we describe a novel method of immunization, using as antigen the EFRH peptide displayed on the surface of the filamentous phage. The EFRH phage evoked effective auto-immune antibodies in amyloid precursor protein [V717I] (APP[V717I]) transgenic mice that recapitulate the amyloid plaques and vascular pathology of Alzheimer’s disease (AD). The immunization provoked a considerable reduction in the number of Aβ amyloid plaques in the brain of the transgenic mice and may serve as the basis for anti-Aβ vaccine.

Statistical aspects of quantitative image analysis of β-amyloid in the APP V717F transgenic mouse model of Alzheimer's disease

Cerebral β-amyloidosis is a central part of the neuropathology of Alzheimer's disease (AD). Quantitation of β-amyloid plaques in the human AD brain, and in animal models of AD, is an important study endpoint in AD research. Methodologic approaches to the measurement of β-amyloid in the brain vary between investigators, and these differences affect outcome measures. Here, one quantitative approach to the measurement of β-amyloid plaques in brain sections was analyzed for sources of variability due to sampling. Brain tissue was from homozygous APP V717F transgenic male mice. Sampling variables were at the mouse and microscopic slide and field levels. Results indicated that phenotypic variability in the mouse sample population was the largest contributor to the standard error of the analyses. Within each mouse, variability between slides or between fields within slides had smaller effects on the error of the analyses. Therefore, when designing studies of adequate power, in this and in other similar models of cerebral β-amyloidosis, sufficient numbers of mice per group must be included in order for change in mean plaque burden attributable to an experimental variable to outweigh phenotypic variability.