Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer's disease.
ABSTRACT: There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.
Project description:BACKGROUND:Extracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown. METHODS:In the present study, the characteristic expressions of MANF in Aβ1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1-42 exposure were also investigated. RESULTS:The results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1-42 exposure, whereas knockdown of MANF has the opposite effect. CONCLUSIONS:These findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.
Project description:The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD.
Project description:The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer's disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo "pool" of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD.
Project description:The accumulation of aggregated amyloid-β (Aβ) in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD), which also includes synaptic impairment, neuroinflammation, neuronal loss, and eventual cognitive defects. Emerging evidence suggests that impairment of Aβ phagocytosis and clearance is a common phenotype in late-onset AD. Rutin (quercetin-3-rutinoside) has long been investigated as a natural flavonoid with different biological functions in some pathological circumstances. Sodium rutin (NaR), could promote Aβ clearance by increasing microglial by increasing the expression levels of phagocytosis-related receptors in microglia. Moreover, NaR promotes a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS (oxidative phosphorylation), which could provide microglia with sufficient energy (ATP) for Aβ clearance. Thus, NaR administration could attenuate neuroinflammation and enhance mitochondrial OXPHOS and microglia-mediated Aβ clearance, ameliorating synaptic plasticity impairment and eventually reversing spatial learning and memory deficits. Our findings suggest that NaR is a potential therapeutic agent for AD.
Project description:Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected (125)I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.
Project description:Alzheimer's disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. The lowered concentrations of acetylcholine (ACh) in AD result in a progressive and significant loss of cognitive and behavioral function. Current AD medications, memantine and acetylcholinesterase inhibitors (AChEIs) alleviate some of these symptoms by enhancing cholinergic signaling, but they are not curative. Since 2003, no new drugs have been approved for the treatment of AD. This article focuses on the current research in clinical trials targeting the neuropathological findings of AD including acetylcholine response, glutamate transmission, Aβ clearance, tau protein deposits, and neuroinflammation. These investigations include acetylcholinesterase inhibitors, agonists and antagonists of neurotransmitter receptors, β-secretase (BACE) or γ-secretase inhibitors, vaccines or antibodies targeting Aβ clearance or tau protein, as well as anti-inflammation compounds. Ongoing Phase III clinical trials via passive immunotherapy against Aβ peptides (crenezumab, gantenerumab, and aducanumab) seem to be promising. Using small molecules blocking 5-HT6 serotonin receptor (intepirdine), inhibiting BACE activity (E2609, AZD3293, and verubecestat), or reducing tau aggregation (TRx0237) are also currently in Phase III clinical trials. We here systemically review the findings from recent clinical trials to provide a comprehensive review of novel therapeutic compounds in the treatment and prevention of AD.
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.
Project description:Cerebral amyloid beta (Aβ) deposits are the main early pathology of Alzheimer's disease (AD). However, abundant Aβ deposits also occur spontaneously in the brains of many healthy people who are free of AD with advancing aging. A crucial unanswered question in AD prevention is why AD does not develop in some elderly people, despite the presence of Aβ deposits. The answer may lie in the composition of Aβ oligomer isoforms in the Aβ deposits of healthy brains, which are different from AD brains. However, which Aβ oligomer triggers the transformation from aging to AD pathogenesis is still under debate. Some researchers insist that the Aβ 12-mer causes AD pathology, while others suggest that the Aβ dimer is the crucial molecule in AD pathology. Aged rhesus monkeys spontaneously develop Aβ deposits in the brain with striking similarities to those of aged humans. Thus, rhesus monkeys are an ideal natural model to study the composition of Aβ oligomer isoforms and their downstream effects on AD pathology. In this study, we found that Aβ deposits in aged monkey brains included 3-mer, 5-mer, 9-mer, 10-mer, and 12-mer oligomers, but not 2-mer oligomers. The Aβ deposits, which were devoid of Aβ dimers, induced glial pathology (microgliosis, abnormal microglia morphology, and astrocytosis), but not the subsequent downstream pathologies of AD, including Tau pathology, neurodegeneration, and synapse loss. Our results indicate that the Aβ dimer plays an important role in AD pathogenesis. Thus, targeting the Aβ dimer is a promising strategy for preventing AD.
Project description:Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.
Project description:The accumulation of intracellular β-amyloid peptide (Aβ) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aβ clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.