Promote Aβ Clearance Research Articles

Wogonin increases β-amyloid clearance and inhibits tau phosphorylation via inhibition of mammalian target of rapamycin: potential drug to treat Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Many molecular lesions have been detected in AD, of which the most commonly observed is the accumulation of misfolded proteins, including β-amyloid (Aβ40 and Aβ42) and tau, in the aging brain. The mammalian target of rapamycin (mTOR) pathway mediates Aβ clearance through autophagy and regulates tau phosphorylation via glycogen synthase kinase-3β (GSK3β). Thus, mTOR becomes an important therapeutic target for AD. However, no mTOR inhibitor has yet been marketed to treat AD. Here, we discovered a natural product, wogonin, which could potently promote Aβ clearance in the primary neural astrocytes and significantly decrease Aβ secretion in SH-SY5Y-APP and BACE1 cells [SH-SY5Y cells stably expressing the human amyloid precursor protein (APP) and β-secretase (BACE1)] through the mTOR/autophagy signaling pathway. Additionally, further research revealed that wogonin inhibited the activity of GSK3β via mTOR inhibition, finally leading to tau phosphorylation reduction in SH-SHY5Y cells and primary neural astrocytes. In conclusion, our study identified a small molecule, wogonin, which could effectively promote Aβ clearance and decrease tau phosphorylation, and highlighted its therapeutic potential for AD treatment.

Potential therapeutic implications of gelsolin in Alzheimer's disease.

The presence of amyloid plaques and vascular amyloid deposits is one of the pathological features of Alzheimer's disease (AD). Amyloid plaques and vascular deposits mainly consist of amyloid-β (Aβ), which is a metabolic product of amyloid-β protein precursor cleaved by β- and γ-secretase. Soluble Aβ monomers readily aggregate into oligomers preceding the formation of insoluble fibrils, and Aβ oligomers are more toxic than fibrils. Intensive therapeutic efforts have been attempted in the treatment of AD targeting Aβ, including preventing Aβ generation, inhibiting Aβ aggregation, and promoting Aβ clearance. The results show that amyloid plaque burden is reduced together with improved cognition performance in AD. Gelsolin, a multifunctional actin-binding protein, exists intracellularly as a cytoplasmic form and extracellularly as a secreted form in blood/cerebrospinal fluid. Gelsolin is suggested to be implicated in AD, based on the findings that some changes of gelsolin are correlated with disease progression rate in AD patients. Gelsolin binds Aβ, inhibits its aggregation into fibrils, and protects cells from apoptosis induced by Aβ. More importantly, administration or overexpression of gelsolin results in significant reduction of amyloid load and decrease of Aβ level in AD transgenic mice. In this article, we review the most recent progress of gelsolin as a potential therapeutic strategy for treatment of AD, and discuss the possible mechanism involved in the clearance of amyloid plaques in AD.

A theoretical study on the molecular determinants of the affibody protein Z(Aβ3) bound to an amyloid β peptide.

Amyloid beta (Aβ) peptides are small cleavage products of the amyloid precursor protein. Aggregates of Aβ peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting Aβ clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein ZAβ3, which binds to an Aβ40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of Aβ40. However, little is known about the energetic contribution of each residue in ZAβ3 to the formation of the (ZAβ3)2:Aβ complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (ZAβ3)2 and those at the exterior and interior faces of Aβ are the main contributors to the binding of (ZAβ3)2 to Aβ. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (ZAβ3)2 to Aβ through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand β-sheet and the π-π stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the ZAβ3 peptide binding to Aβ.

Ginsenoside compound K promotes β-amyloid peptide clearance in primary astrocytes via autophagy enhancement.

The aim of the present study was to investigate the effect of ginsenoside compound K on β-amyloid (Aβ) peptide clearance in primary astrocytes. Aβ degradation in primary astrocytes was determined using an intracellular Aβ clearance assay. Aggregated LC3 in astrocyte cells, which is a marker for the level of autophagy, was detected using laser scanning confocal microscope. The effect of compound K on the mammalian target of rapamycin (mTOR)/autophagy pathway was determined using western blot analysis, and an enzyme-linked immunosorbent assay was used for Aβ detection. The results demonstrated that compound K promoted the clearance of Aβ and enhanced autophagy in primary astrocytes. In addition, it was found that phosphorylation of mTOR was inhibited by compound K, which may have contributed to the enhanced autophagy. In conclusion, compound K promotes Aβ clearance by enhancing autophagy via the mTOR signaling pathway in primary astrocytes.

Transthyretin Stabilization by Iododiflunisal Promotes Amyloid-β Peptide Clearance, Decreases its Deposition, and Ameliorates Cognitive Deficits in an Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.

Update on Alzheimer’s Disease Therapeutics

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Clinically, it is characterized by progressive cognitive impairment and the emergence of neuropsychiatric disturbances. In recent years, many drug candidates aimed at disease modification have advanced into large, randomized controlled trials, but none have demonstrated efficacy in slowing down the relentless progression of AD. While the exact cause of AD is still being fervently investigated, the field is moving toward earlier identification and treatment of the disease, as it is believed this may be the main reason for so many clinical trial failures. There are currently four main mechanisms of action that are being actively developed in AD therapeutics: Drugs aimed at reducing Aβ production, notably secretase inhibitors; Drugs aimed at reducing Aβ plaque burden via inhibition of aggregatio or disruption of aggregates; Drugs aimed at promoting Aβ clearance via active or passive immunotherapy; and Drugs aimed at preventing tau protein phosphorylation. In this review, recent findings from clinical and preclinical studies in each of these categories will be discussed, as well as a category entitled ' other therapies,' that includes treatments that do not fit under a single mechanism of action, but represent rational interventions for the underlying pathology of Alzheimer's disease.

Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer's Disease Model Mice Targeting Both -Amyloid Production and Clearance

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

Cudrania cochinchinensis attenuates amyloid β protein-mediated microglial activation and promotes glia-related clearance of amyloid β protein

BackgroundMicroglial inflammation may significantly contribute to the pathology of Alzheimer’s disease. To examine the potential of Cudrania cochinchinensis to ameliorate amyloid β protein (Aβ)-induced microglia activation, BV-2 microglial cell line, and the ramified microglia in the primary glial mixed cultured were employed.ResultsLipopolysaccharide (LPS), Interferon-γ (IFN-γ), fibrillary Aβ (fAβ), or oligomeric Aβ (oAβ) were used to activate microglia. LPS and IFN-γ, but not Aβs, activated BV-2 cells to produce nitric oxide through an increase in inducible nitric oxide synthase (iNOS) expression without significant effects on cell viability of microglia. fAβ, but not oAβ, enhanced the IFN-γ-stimulated nitric oxide production and iNOS expression.The ethanol/water extracts of Cudrania cochinchinensis (CC-EW) and the purified isolated components (i.e. CCA to CCF) effectively reduced the nitric oxide production and iNOS expression stimulated by IFN-γ combined with fAβ. On the other hand, oAβ effectively activated the ramified microglia in mixed glial culture by observing the morphological alteration of the microglia from ramified to amoeboid. CC-EW and CCB effectively prohibit the Aβ-mediated morphological change of microglia. Furthermore, CC-EW and CCB effectively decreased Aβ deposition and remained Aβ in the conditioned medium suggesting the effect of CC-EW and CCB on promoting Aβ clearance. Results are expressed as mean ± S.D. and were analyzed by ANOVA with post-hoc multiple comparisons with a Bonferroni test.ConclusionsThe components of Cudrania cochinchinensis including CC-EW and CCB are potential for novel therapeutic intervention for Alzheimer’s disease.

The science of repurposing drugs in Alzheimer's disease therapeutics: The tale of rexinoid receptor ligand IRX4204

Alzheimer's disease (AD) is a multifaceted disease with different pathological features. Retinoid X receptor (RXR) is a nuclear receptor that can be activated by 9‐cis retionoic acid. RXR agonists are emerging as a new class of agents capable of promoting Aβ clearance by enhancing expression of ApoE that traffics Aβ. IRX4204 is a rexinoid agonist with high potency and selectivity to RXRs and an extensive history of safety in oncology clinical trials. In this study, we tested the effect of IRX4204 on amyloid‐mediated neuropathology and cognitive impairments in an animal model of AD. We found that IRX4204 can effectively pass the blood brain barrier and accumulate in the brain at a concentration sufficient to activate the CREB signaling pathway in vitro. IRX4204 can interfere with Aβ and tau oligomerization, promote ApoE protein expression, and improve synaptic plasticity. Moreover, in vivo IRX4204 treatment can significantly improve cognitive function and reduce neuropathology in TgCRND8 mouse model of AD. Our study demonstrated IRX4204 can be potentially developed into a disease‐modifying agent and provided impetus for immediate testing of IRX4204 in clinical settings for AD prevention and treatment.

Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist

The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

The binding of resveratrol to monomer and fibril amyloid beta

As currently understood, Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is driven by the aggregation of amyloid beta (Aβ) protein. It has been shown that resveratrol (RES) may attenuate amyloid β peptide-induced toxicity, promote Aβ clearance and reduce senile plaques. However, it remains to be determined whether RES could interact directly with Aβ. The aim of the present study was to examine the direct binding of RES to monomer and fibril Aβ. Using surface plasmon resonance (SPR) and proton nuclear magnetic resonance (1H NMR), our results identified the direct binding of RES to Aβ. The ability of RES to bind to both fibril and monomer Aβ(1–40 and 1–42) was further analyzed by SPR. The binding response of RES to fAβ(1–42) was higher than that to monomer Aβ(1–42), whereas the binding response of RES to fAβ(1–40) was lower than that to monomer Aβ(1–40). The KD of RES for fibril Aβ(1–40 or 1–42) was higher than that for the corresponding monomer Aβ. Compared to the control compound Congo red (CR), the binding responses of RES to monomer Aβ(1–42) and Aβ(1–40) were stronger, but binding to fibril Aβ(1–42) was weaker, and the KDs of RES with both monomer and fibril Aβ(1–40) and Aβ(1–42) were higher than that of CR. When Aβ(1–40 or 1–42) was co-incubated with RES (50μM), the thioflavin T fluorescence of the mixture was weakened, and the number and length of amyloid fibrils were decreased. Furthermore, the results of staining in consecutive brain slices from AD patients showed that RES (10−4M) could stain senile plaques. These results indicated that RES could bind directly to Aβ in different states, which may provide new insight into the protective properties of RES against AD.

Activation of the CB2 receptor system reverses amyloid-induced memory deficiency

Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)—a novel selective CB2 agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB2 receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance

Accumulation of β-amyloid (Aβ) peptide in the brain is a major hallmark of Alzheimer's disease. An optimal brain insulin level promotes Aβ clearance, which may play protective roles against Alzheimer's disease. In this study we examined the role of dietary conditions leading to insulin resistance on amyloidosis in fructose-drinking rats. Further investigations tested pioglitazone, an insulin sensitizer, intervention on the altered amyloidosis in this rodent model of insulin resistance. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups (n = 10): non-treated and water-drinking rats (control group); pioglitazone treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10 mg/kg d by gavage for the last 12 weeks of the 16-week period. We found that diet-induced insulin resistance induced Aβ overproduction with altered expression of Aβ metabolism-associated molecules, which corresponded with increased β-secretase-1 (BACE1), γ-secretase (PS-1) activities and decreased insulin degrading enzyme (IDE) activities, but not neprilysin in the cortex and hippocampus. Additionally, pioglitazone treatment prevented all these observed abnormalities. This study indicates that insulin resistance induced by fructose-drinking affects the expression of Aβ metabolism-associated molecules that are responsible for Aβ deposition and pioglitazone treatment negatively modulate amyloidogenesis.

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease

BackgroundAlzheimer's disease (AD) is an age-related neurodegenerative disorder associated with brain innate immune activation mainly mediated by microglia. These cells are known to be activated in the brain of AD patients and to produce inflammatory cytokines and neurotoxic molecules in response to Amyloid beta (Aβ). Activation of microglia can also promote Aβ clearance via Toll-like receptors (TLRs). Myeloid differentiation factor 88 (MyD88) is the adaptor molecule for most of these innate immune receptors, transducing the intracellular signal from TLRs to nucleus.ResultsHere, we report that more than 50% reduction in MyD88 expression in a mouse model of AD accelerated spatial learning and memory deficits. Brain of APPswe/PS1-MyD88+/- mice was characterized by a delay in accumulation of Aβ plaques and increased soluble levels of Aβ oligomers. Furthermore, inflammatory monocyte subset and brain IL-1β gene expression were significantly reduced in APPswe/PS1 mice with impaired MyD88 signaling.ConclusionsThese data indicate that activation of MyD88 intracellular signaling pathway, likely by TLRs, acts as a natural innate immune mechanism to restrict disease progression of APPswe/PS1 mice.

Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease

Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Aβ peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Aβ clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Aβ clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Aβ42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Aβ40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Aβ42 and may represent a novel therapeutic approach to Alzheimer's disease.

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.

Degradation of the Alzheimer Disease Amyloid β-Peptide by Metal-dependent Up-regulation of Metalloprotease Activity

Biometals play an important role in Alzheimer disease, and recent reports have described the development of potential therapeutic agents based on modulation of metal bioavailability. The metal ligand clioquinol (CQ) has shown promising results in animal models and small phase clinical trials; however, the actual mode of action in vivo has not been determined. We now report a novel effect of CQ on amyloid beta-peptide (Abeta) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu(2+) or Zn(2+) resulted in an approximately 85-90% reduction of secreted Abeta-(1-40) and Abeta-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted Abeta was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu(2+). MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu(2+) also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of Abeta-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of Abeta deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.