Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer’s Disease

The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer’s disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain.     

Regulation of extracellular Zn2+ homeostasis in the hippocampus as a therapeutic target for Alzheimer’s disease

Introduction: The hippocampus plays an important role in spatial and declarative memory. Zn²⁺ is released from glutamatergic (zincergic) neuron terminals in the hippocampus and serves as a signal factor. Synaptic Zn²⁺ homeostasis is critical for cognitive activity in the hippocampus. Amyloid-β (Aβ) is a candidate for the pathogenesis of Alzheimer’s disease (AD) and interacts with Zn²⁺.

Areas covered: This paper gives an overview of the interaction between Aβ and Zn²⁺ in the extracellular compartment in the pathophysiology of AD. Aβ is aggregated with Zn²⁺ and the aggregation of Aβ-peptides is widely considered to be the critical step in the pathogenesis of AD. The reader will gain an understanding of recent studies on the importance of the interaction of Aβ with Zn²⁺ in the pathophysiology and therapeutic strategy of AD. Extracellular Zn²⁺ in the hippocampus is a therapeutic target for AD.

Expert opinion: Recent studies show that the inhibition of the interaction of Aβ with extracellular Zn²⁺ ameliorates the pathophysiology of AD and that extracellular Zn²⁺ in the hippocampus is involved in transiently Aβ-induced cognition deficits. Zn²⁺ may play as a key-mediating factor in pathophysiology in which Aβ is involved and is a targeting molecule to prevent the pathogenesis of AD.     

脑内β淀粉样蛋白水平的调节

β淀粉样蛋白（βamyloid protein,Aβ）是体内重要生物活性物质,主要包括Aβ40和Aβ42,它们在体内的利与害取决于其浓度高低。生理条件下脑内Aβ通过两个平衡维持在一定水平上,第一个平衡是Aβ的生成和降解,β分泌酶和γ分泌酶参与Aβ的生成,而脑啡肽酶和胰岛素降解酶参与Aβ的降解;第二个平衡是Aβ跨越血脑屏障的内向转运和外向转运,高级糖基化终产物受体（RAGE）是血脑屏障上Aβ内向转运体,而低密度脂蛋白受体相关蛋白1（LRP1）是血脑屏障上Aβ外向转运体。如果这两个平衡任何一个被破坏,将会导致脑内Aβ水平异常升高,继而Aβ聚集和沉淀,形成老年斑。本文综述生理条件下脑内Aβ水平的调节以及降低病理状态下脑内Aβ水平的策略。     

ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice

Alzheimer’s disease (AD) is characterized by impaired clearance of amyloid beta (Aβ) peptides, leading to the accumulation of Aβ in the brain and subsequent neurodegeneration and cognitive impairment. ApoE plays a critical role in the proteolytic degradation of soluble forms of Aβ. This effect is dependent upon lipidation of ApoE by ABCA1-mediated transfer of phospholipids and cholesterol. ApoE and ABCA1 are induced by the action of the RXR agonist, bexarotene. We have previously shown that bexarotene reduces Aβ levels in AD mouse models and we have hypothesized that this effect requires ABCA1-mediated lipidation of ApoE. To test this hypothesis, we crossed ABCA1-deficient (ABCA1 KO) mice with the APP/PS1 model of AD. Aged ABCA1 WT and ABCA1 KO APP/PS1 mice were treated for 7 days with vehicle or bexarotene (100 mg/kg/day). Bexarotene reduced levels of soluble Aβ 1–40 and 1–42 in the hippocampus of ABCA1 WT but not ABCA1 KO APP/PS1 mice. In contrast, insoluble levels of Aβ, and plaque loads were unaffected by bexarotene in this study. ABCA1 KO mice had increased levels of inflammation compared with ABCA1 WT mice. Bexarotene also increased most inflammatory gene markers evaluated. The effect of bexarotene on microglial inflammatory profiles, however, was independent of ABCA1 genotype. Importantly, bexarotene ameliorated deficits in novel object recognition in ABCA1 WT but not ABCA1 KO APP/PS1 mice. These data indicate that ABCA1-induced lipidation of ApoE is necessary for the ability of bexarotene to clear hippocampal soluble Aβ and ameliorate cognitive deficits.     

Small-molecule inhibitors/modulators of amyloid-β peptide aggregation and toxicity for the treatment of Alzheimer's disease: a patent review (2010 – 2012)

Introduction: Genetic, physiological, and biochemical data indicate that agglomerates of the 42-amino acid form of the amyloid-β (Aβ₄₂) peptide are strongly linked to Alzheimer's disease (AD) etiology and thus represent a particularly attractive target for the development of an effective disease-modifying approach for AD treatment. A plethora of chemical entities able to modulate Aβ₄₂ self-assembly have been developed in recent years, among them, several are in clinical or preclinical development.

Areas covered: This review accounts for small-molecule inhibitors of Aβ peptide polymerization and toxicity, reported in the patent literature during the 2010 – 2012 period, and their potential use as disease-modifying therapeutics for AD cure.

Expert opinion: The earliest pathogenic event is the formation of soluble Aβ oligomers that disrupt synaptic communication. Drug design strategies targeting these primary toxic agents could hold considerable promises for obtaining effective anti-AD drugs candidate. The heterogeneous aggregation of Aβ and the resulting difficulty to structurally characterize the peptide represent important drawbacks.     

Compounds for imaging amyloid-β deposits in an Alzheimer’s brain: a patent review

Introduction: β-amyloid (Aβ) plaques in the brain are regarded as a hallmark of Alzheimer’s disease (AD), and the imaging of Aβ is a critical step for early diagnosis. Extensive research has been done to develop probes for targeting Aβ with available imaging modalities.

Areas covered: In this review, the authors give an overview of published patents and papers about the discovery and development of compounds possessing potential utilization in imaging Aβ for the diagnosis of AD. SciFinder is the main electronic database for patent study in this review.

Expert opinion: Despite achievements in Aβ imaging, there is still a need to develop innovative compounds with selectivity and high affinity to Aβ. Positron emission tomography imaging agents will still be the trend in the field in the short term. Due to the low costs for single-photon emission computed tomography (SPECT) and the excellent nuclear properties of ^99mTc, substantial research should be conducted on the development of the probes for SPECT. Refining the current imaging techniques and in the meantime developing new efficient imaging multimodality and compounds would be a promising approach to imaging Aβ.     

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.Key words: Breast cancer brain metastases, Blood‒brain barrier, Amyloid beta, Abluminal LRP1, Brain clearance, Fusion peptide, MMP, Nanoparticles-lysine); PLL, poly(ε-carbobenzoxy-l-lysine); PVA, polyvinyl alcohol; s, sensitive VPMS-MRGG; SDS, sodium dodecyl sulfate; t_1/2, half time; tPA, tissue plasminogen activator     

Endothelin receptor antagonists: Potential in Alzheimer's disease

Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction correlating with the impairment of cognition. There is evidence that cerebral hypoperfusion precedes and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs neuronal function, reduces the clearance of Aβ peptide and other toxic metabolites from the brain, and upregulates Aβ production. Studies in animal models of AD have shown the reduction in CBF to be more than would be expected for the reduction in neuronal metabolic activity. Aβ may contribute to the reduction in CBF in AD, as both Aβ_1–40 and Aβ_1–42 induce cerebrovascular dysfunction. Aβ_1–40 acts directly on cerebral arteries to cause cerebral smooth muscle cell contraction. Aβ_1–42 causes increased neuronal production and release of endothelin-1 (ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that upregulation of the ECE-2–ET-1 axis by Aβ_1–42 contributes to the chronic reduction of CBF in AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest that endothelin receptor antagonists may be beneficial in maintaining CBF in AD.     

Protective effect of centipedegrass against Aβ oligomerization and Aβ-mediated cell death in PC12 cells

Abstract

Context: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal accumulation of β-amyloid (Aβ). Multiple Aβ-aggregated species have been identified, and neurotoxicity appears to be correlated with the amount of non-fibrillar oligomers. Potent inhibitors of Aβ oligomer formation or Aβ-induced cell toxicity have emerged as attractive means of therapeutic intervention. Eremochloa ophiuroide Hack. (Poaceae), also known as centipedegrass (CG), originates from China and South America and is reported to contain several C-glycosyl flavones and phenolic constituents.

Objective: We investigated whether CG could suppress Aβ aggregation, BACE1 activity, and toxicity at neuronal cell.

Materials and methods: The inhibitory effect of CG extracts toward aggregation of Aβ42 was investigated in the absence and presence of 50?µg/mL CG. We investigated the inhibitory effects of CG (0–5?µg/mL) on BACE1 using fluorescence resonance energy transfer (FRET)-based assay. The effects of CG (0–75?µg/mL) on Aβ42-induced neurotoxicity were examined in PC12 cells in the presence or absence of maysin and its derivatives of CG.

Results: We isolated EA-CG fraction (70% MeOH fraction from EtOAc extracts) from methanol extracts of CG, which contained approximately 60% maysin and its derivatives. In the present studies, we found that several Aβ oligomeric forms such as the monomer, dimer, trimer, and highly aggregated oligomeric forms were remarkably inhibited in the presence of 50?µg/mL of EA-CG. EA-CG also inhibited BACE1 enzyme activity in a dose-dependent manner. EA-CG treatment generated approximately 50% or 85% inhibition to the control at the tested concentrations of 1 or 5?µg/mL, respectively. Moreover, the neurotoxicity induced by Aβ42 was significantly reduced by treatment of EA-CG, and the 75?µg/mL EA-CG treatment significantly increased cell viability up to 82.5%.

Discussion and conclusion: These results suggested that the anti-Alzheimer’s effects of CG occurred through inhibition of neuronal cell death by intervening with oligomeric Aβ formation and reducing BACE1 activity. Maysin in CG could be an excellent therapeutic candidate for the prevention of AD.     

Neuroprotective effects of a biodegradable poly(lactic-co-glycolic acid)-ginsenoside Rg3 nanoformulation: a potential nanotherapy for Alzheimer’s disease?

It is well established that overproduction and accumulation of the β-amyloid (Aβ) peptide 1–42 (Aβ(1–42)) is a trigger of the pathological cascade in Alzheimer’s disease (AD) that manifests as cognitive impairment. Ginsenoside Rg3 is an important constituent of ginseng, plays an essential role in memory and improved cognition, and is known to produce antioxidant effects via the reduction of free radicals. Therefore, ginsenoside Rg3 may be a promising candidate as a neuroprotective agent for the treatment of AD. A novel nanotherapeutic strategy that enhances delivery of ginsenosides to the brain by increasing its transport across the blood brain barrier (BBB) would facilitate neuroprotection and limit the accumulation of Aβ plaques and subsequent neurodegeneration. In this current study, we formulated and characterised biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that encapsulate ginsenoside Rg3 and Thioflavin T, an Aβ diagnostic; examine its neuroprotective effects; investigate key mechanisms that may underlie its neuroprotective effects; and evaluate its ability to cross the BBB using an in vitro BBB model. Our PLGA-Rg3 NPs offers an exciting new theranostic material capable of encapsulating natural nutraceuticals for the detection and treatment of AD. In addition, this nanotechnology strategy can be adapted to treat other neurological diseases, utilising many natural therapeutic agents which are limited by their solubility and/or poor pharmacokinetics.     

Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012

Introduction: γ-Secretase is the enzyme responsible for the final step of amyloid precursor protein proteolysis to generate Aβ peptides including Aβ42 which is believed to be a toxic species involved in Alzheimer's disease (AD) progression. γ-Secretase modulators (GSMs) have been shown to selectively lower Aβ42 production without affecting total Aβ levels or the formation of γ-secretase substrate intracellular domains such as APP intracellular domain and Notch intracellular domain. Therefore, GSMs have emerged as an important therapeutic strategy for the treatment of AD.

Areas covered: The literature covering novel GSMs will be reviewed focusing on patents from 2010 to 2012.

Expert opinion: During the last review period (2008 – 2010) considerable progress was made developing GSMs with improved potency for lowering Aβ42 levels, but most of the compounds resided in unfavorable central nervous system (CNS) drug space. In this review period (2010 – 2012), there is a higher percentage of potent GSM chemical matter that resides in favorable CNS drug space. It is anticipated that clinical candidates will emerge out of this cohort that will be able to test the GSM mechanism of action in the clinic.     

The road to load late-onset Alzheimer's disease and a possible way to block it

The ageing brain becomes increasingly less able to destroy or eject toxic amyloid (A) β42 peptide byproducts of normal neuronal activity that consequently accumulate to induce Alzheimer's disease (AD). Therefore, the various components of the Aβ-clearing machinery are prime targets for AD therapeutics. In this connection, there are reports that taking statins to lower circulating cholesterol to prevent cardiovascular disease can also prevent late-onset AD (LOAD) the most common form of the disease. However, it seems unlikely that statins would prevent LOAD by lowering the very long-lived brain cholesterol that is controlled independently from the very much shorter-lived circulating cholesterol. In fact, reducing the ability of the brain astrocytes to make cholesterol for their closely associated neuron clients' synaptogenesis could damage the brain rather than protect it. However, a plausible way statins might prevent LOAD is to target a main component of the clearance machinery, low-density lipoprotein receptor-related protein 1 (LRP1), the brain's powerful Aβ-efflux driver. This is indicated by a reported ability of micromolar concentrations of lovastatin and simvastatin to strongly stimulate brain vascular endothelial cells to make this Aβ ejector. Therefore, if this holds up, taking a statin over the years would prevent the normal decline of LRP1 in the ageing brain and a LOAD-driving accumulation of Aβ.     

Preclinical to phase II amyloid beta (Aβ) peptide modulators under investigation for Alzheimer’s disease

Introduction: Alzheimer disease (AD) is the most common form of dementia and its incidence is increasing at an alarming rate all over the world. The pathophysiology of AD is characterized by chronic, progressive neurodegeneration which involves early synaptotoxicity. One of the most obvious pathological feature of AD is the accumulation of amyloid-β (Aβ) in the brain. Since current treatment options only provide symptomatic help and Aβ is thought to underlie early synaptic pathology, Aβ reduction or modulation in the brain may be a promising therapeutic strategy in preventing and /or reversing AD-related dysfunction.

Areas covered: This paper outlines and evaluates the current landscape of preclinical and clinical studies focusing on modulating Aβ pathophysiology. Data and analysis for this review were procured from PubMed, clinicaltrials.gov and Alzforum.

Expert opinion: According to current knowledge, reducing Aβ production offers numerous treatment options. However, targeting the initial steps by pharmacological interference with secretases is challenging due to the emergence of various side effects. The most promising approach seems to be the prevention of early Aβ oligomerization. Combination approaches targeting both Aβ and tau would seem to be another promising strategy that could have beneficial effects through the course of the disease.     

TGF-β signalling and immunity in prostate tumourigenesis

Importance of the field: The TGF-β's are pleiotropic cytokines that regulate multiple cellular functions. Their role in the prostate is important for normal prostate development and also in prostate tumourigenesis.

Areas covered in this review: The interactions TGF-β-mediated signalling has with maintaining prostate health, as well as its role in prostate tumourigenesis and prostate tumour immune evasion, with emphasis on how a breakdown in these interactions may influence disease progression.

What the reader will gain: That TGF-β influences normal prostate growth and differentiation by regulating the balance between epithelial cell proliferation and apoptosis, and involving the androgen receptor pathway. That TGF-β protects and maintains prostate stem cells and a review of the contrasting role TGF-β has in prostate tumourigenesis and tumour development, where TGF-β acts as a tumour suppressor and then switches roles to become a tumour promoter, and creates a local immunosuppressive niche leading to systemic tumour tolerance.

Take home message: TGF-β signalling in prostate cancer is a valid target for the treatment of this disease; however any therapeutic regimen will require an understanding of all aspects of the TGF-β-signalling nexus, otherwise by the very pleiotrophic nature of TGF-β, limited clinical benefits may result.     

Estrogen receptor β selective nonsteroidal estrogens: seeking clinical indications

Importance of the field: Nonsteroidal estrogens have been known since the 1930s. However, the relatively recent (1996) discovery of estrogen receptor subtype β (ERβ) suggested a possible paradigm shift away from SERM-like selectivity. Selective ERβ agonism would potentially allow expansion of estrogenic targeting into new indications (discussed herein) currently precluded by the thrombogenic and hyperproliferative effects of nonselective estrogens.

Areas covered in this review: ERβ agonist design has been very successful. Pharmacophores for ERβ selective nonsteroidal estrogens are generally diphenolic compounds that achieve an inter-phenolic distance and geometry similar to 17β-estradiol with few restraints on the nature of the element linking the phenols (or phenol mimetics). The tremendously chemodiverse ERβ agonist patent literature is reviewed, segregating the agonists into structurally similar compounds based on their interphenolic linking elements.

What the reader will gain: A comprehensive understanding of the chemotype landscape of this field and an assessment of its maturation.

Take home message: Subtype selective ERβ agonist therapy seems very promising. However, more clinical testing is needed to firmly establish its therapeutic potential. At this point, ERβ is a promising target in search of an indication.     

Immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.     

Inhaled essential oil from Chamaecyparis obtuse ameliorates the impairments of cognitive function induced by injection of β-amyloid in rats

Context: Chamaecyparis obtusa Sieb. & Zucc., Endlicher (Cupressaceae) forest bathing or aromatherapy has been shown in various studies to have biological functions such as anticancer, antiallergies, antiinflammatory, and antioxidant activity. However, no reports exist on the pharmacological or biological activities of the essential oil of C. obtusa (EOCO) or its effects on central nervous system.

Objective: The aggregation and formation of β-amyloid peptides (Aβ) into fibrils are central events in the pathogenesis of Alzheimer’s disease (AD), and overproduction and aggregation of Aβ into oligomers have been known to trigger neurotoxicity. In this study, we investigated the effects of inhaled EOCO on cognitive function and neuronal apoptosis in rats intrahippocampally injected with Aβ.

Materials and methods: To model AD, 4 μg of aggregated Aβ was injected into the hippocampus. To test the effects of EOCO, behavioral performance in the Morris water maze was tested 4 days after injection. After behavioral testing, brain sections were prepared for TTC staining and TUNEL assay.

Results: Inhaled EOCO protected spatial learning and memory from the impairments induced by Aβ_1–40 injection. In addition, the behavioral deficits accompanying Aβ_1–40-induced AD were attenuated by inhalation of EOCO. Furthermore, acetylcholinesterase (AChE) activity and neuronal apoptosis were significantly inhibited in rats treated with Aβ_1–40 and EOCO compared to rats treated only with Aβ_1–40.

Discussion and conclusion: EOCO suppressed both AD-related neuronal cell apoptosis and AD-related dysfunction of the memory system. Thus, the results of this study support EOCO as a candidate drug for the treatment of AD.     

Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.