Exploring glia to better understand Alzheimer’s disease

The amyloid-β (Aβ) hypothesis has been the leading explanation for the pathogenesis of Alzheimer’s disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aβ. Aβ aggregates activate glial cells, which in turn remove Aβ. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.     

Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

The EC (entorhinal cortex) is fundamental for cognitive and mnesic functions. Thus damage to this area appears as a key element in the progression of AD (Alzheimer''s disease), resulting in memory deficits arising from neuronal and synaptic alterations as well as glial malfunction. In this paper, we have performed an in-depth analysis of astroglial morphology in the EC by measuring the surface and volume of the GFAP (glial fibrillary acidic protein) profiles in a triple transgenic mouse model of AD [3xTg-AD (triple transgenic mice of AD)]. We found significant reduction in both the surface and volume of GFAP-labelled profiles in 3xTg-AD animals from very early ages (1 month) when compared with non-Tg (non-transgenic) controls (48 and 54%, reduction respectively), which was sustained for up to 12 months (33 and 45% reduction respectively). The appearance of Aβ (amyloid β-peptide) depositions at 12 months of age did not trigger astroglial hypertrophy; nor did it result in the close association of astrocytes with senile plaques. Our results suggest that the AD progressive cognitive deterioration can be associated with an early reduction of astrocytic arborization and shrinkage of the astroglial domain, which may affect synaptic connectivity within the EC and between the EC and other brain regions. In addition, the EC seems to be particularly vulnerable to AD pathology because of the absence of evident astrogliosis in response to Aβ accumulation. Thus we can consider that targeting astroglial atrophy may represent a therapeutic strategy which might slow down the progression of AD.     

Loading into Nanoparticles Improves Quercetin's Efficacy in Preventing Neuroinflammation Induced by Oxysterols

Chronic inflammatory events appear to play a fundamental role in Alzheimer''s disease (AD)-related neuropathological changes, and to result in neuronal dysfunction and death. The inflammatory responses observed in the AD brain include activation and proliferation of glial cells, together with up-regulation of inflammatory mediators and of free radicals. Along with glial cells, neurons themselves can also react and contribute to neuroinflammatory changes in the AD brain, by serving as sources of inflammatory mediators. Because excess cholesterol cannot be degraded in the brain, it must be excreted from that organ as cholesterol oxidation products (oxysterols), in order to prevent its accumulation. Among risk factors for this neurodegenerative disease, a mechanistic link between altered cholesterol metabolism and AD has been suggested; oxysterols appear to be the missing linkers between the two, because of their neurotoxic effects. This study shows that 24-hydroxycholesterol, 27-hydroxycholesterol, and 7β-hydroxycholesterol, the three oxysterols potentially implicated in AD pathogenesis, induce some pro-inflammatory mediator expression in human neuroblastoma SH-SY5Y cells, via Toll-like receptor-4/cyclooxygenase-2/membrane bound prostaglandin E synthase (TLR4/COX-2/mPGES-1); this clearly indicates that oxysterols may promote neuroinflammatory changes in AD. To confirm this evidence, cells were incubated with the anti-inflammatory flavonoid quercetin; remarkably, its anti-inflammatory effects in SH-SY5Y cells were enhanced when it was loaded into β-cyclodextrin-dodecylcarbonate nanoparticles, versus cells pretreated with free quercetin. The goal of loading quercetin into nanoparticles was to improve its permeation across the blood-brain barrier into the brain, and its bioavailability to reach target cells. The findings show that this drug delivery system might be a new therapeutic strategy for preventing or reducing AD progression.     

Luteinizing hormone: Evidence for direct action in the CNS

This article is part of a Special Issue “SBN 2014”.Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic–pituitary–gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.     

Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease

Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β‐amyloid (Aβ) production and inhibit neuroinflammation. However, follow‐up clinical trials, mostly using selective cyclooxygenase (COX)‐2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX‐1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro‐inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX‐1 inhibition, rather than COX‐2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20‐month‐old triple transgenic AD (3 × Tg‐AD) mice with the COX‐1 selective inhibitor SC‐560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC‐560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg‐AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX‐1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg‐AD mice. Thus, selective COX‐1 inhibition should be further investigated as a potential therapeutic approach for AD.     

TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ(1-40) and Aβ(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.     

A combination of lycopene and human amniotic epithelial cells can ameliorate cognitive deficits and suppress neuroinflammatory signaling by choroid plexus in Alzheimer's disease rat

Neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to be correlated with cognitive deficits in Alzheimer's disease (AD). Previously, some studies have demonstrated that lycopene (LYCO) or human amniotic epithelial cells (HAECs) could attenuate inflammation in AD. Specifically, the choroid plexus (CP), an epithelial layer that forms the blood-cerebrospinal fluid barrier, is able to modulate the cognitive function, through changes in the neuroinflammatory response and in brain immune surveillance. However, it is unclear if LYCO can interact with HAECs to improve neuroinflammation at the CP. Thus, this study chose the region of interest, considered the feasibility of using a combination of LYCO and HAECs, as a therapeutic agent for immunomodulatory effects at the CP in an acutely induced AD rat model. Results showed that oral administration of LYCO, HAECs transplantation, and their combination significantly improved cognitive deficits in water maze test, decreased the level of proinflammatory mediators (TNF-α and IL-1β), increased the level of anti-inflammatory mediators (IL-10 and TGF-β1) in the cerebro-spinal fluid, and hippocampal tissue. Interestingly, LYCO administration, HAECs transplantation and their combination reversed the Aβ_1–42 induced up-regulation of Toll like receptor 4 and nuclear factor-κB p65 mRNA and protein expressions at the CP. This study provided the novel experimental evidence for the influence of co-treatment with LYCO and HAECs on immunomodulatory capabilities of CP. It could also warrant therapeutic window for the pathophysiology of AD and the associated underlying mechanisms at the CP.     

Stem cell therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell–derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.     

Dendritic Cells as an Alternate Approach for Treatment of Neurodegenerative Disorders

Despite years of research, Alzheimer’s disease (AD) remains incurable and thus poses a major health challenge in coming years. This neurodegenerative disease belongs to a heterogeneous group of human tauopathies, characterized by the extracellular deposition of beta amyloid-Aβ and intracellular accumulation of tau protein in neuronal and glial cells, whereby tau pathology best correlates with disease progression. For decades, several disease-modifying agents were brought to clinical studies with promising efficacy in preclinical trials; however, all of the subsequent clinical trials failed. Therefore, the pursuit for therapeutic agents for the treatment of AD and other tauopathies still continue. Recent evidences show previously unidentified role of peripheral immune system in regulating the inflammatory status of the brain, mainly the dendritic cells. A decrease in functionality and count of dendritic cells has been observed in Alzheimer’s disease. Here, we discuss a potential role of dendritic cell-based vaccines as therapeutic approach in ameliorating disease pathogenesis in AD and other tauopathies.     

Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis

The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD.     

骨钙素的中枢调控作用及其生物学机制

骨钙素(OCN)能调节多种外周组织器官的生理结构与功能,也发挥重要的中枢调控作用,与个体的学习和记忆等高级认知功能密切相关。研究表明,OCN穿过血脑屏障进入大脑,并与神经元或神经胶质细胞膜上的G蛋白偶联受体(GPCR)家族成员GPR158和GPR37结合,激活或抑制细胞内相关信号通路,改变神经元或神经胶质细胞的生理活性。OCN在脑内的作用主要包括调节5-羟色胺、多巴胺、去甲肾上腺素和γ-氨基丁酸等神经递质合成与释放、增加脑源性神经营养因子表达、促进海马神经发生、增强海马神经元自噬及维持髓鞘稳态等。此外,OCN还能参与调控多种神经退行性疾病的病理生理学进程。在阿尔茨海默病(AD)中,OCN干预能够部分减少β-淀粉样蛋白(Aβ)沉积及Aβ诱发的细胞毒性等,改善学习和记忆能力缺陷;在帕金森氏病(PD)中,OCN干预能够部分抑制黑质和纹状体多巴胺能神经元丢失,增加酪氨酸羟化酶含量及降低神经炎症等,缓解运动功能障碍。本文通过解析GPR158和GPR37的结构与功能,分析OCN在脑内的作用及其生物学机制,探讨OCN对AD和PD等神经退行性疾病的影响,为进一步筛选促进脑健康的新型靶点提供依据。     

Neuroinflammation and Memory: The Role of Prostaglandins

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators within the brain, and recruitment of peripheral immune cells. Interestingly, memory deficits have been observed following many inflammatory states including infection, traumatic brain injury (TBI), normal aging, and Alzheimer’s disease (AD). Prostaglandins (PGs), a class of lipid mediators which can have inflammatory actions, are upregulated by these inflammatory challenges and can impair memory. In this paper, we critically review the success of nonsteroidal anti-inflammatory drugs, which prevent the formation of PGs, in preventing neuroinflammation-induced memory deficits following lipopolysaccharide injection, TBI, aging, and experimental models of AD in rodents and propose a mechanism by which PGs could disrupt memory formation.     

Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease

Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.     

Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aβ deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.     

Regulatory region of human amyloid precursor protein (APP) gene promotes neuron-specific gene expression in the CNS of transgenic mice.

The accumulation of beta-amyloid protein in specific brain regions is a central pathological feature of Alzheimer's disease (AD). The 4 kd beta-amyloid protein derives from a larger amyloid precursor protein (APP) by as yet unknown mechanisms. In the absence of a laboratory animal model of AD, transgenic mice expressing various APP gene products may provide new insights into the relationship between APP and beta-amyloid formation and the pathogenesis of AD. beta-amyloid accumulation in AD brain may result from interactions between APP and other molecules. Such interactions are likely to be developmentally regulated and tissue-specific. A transgenic mouse model of AD, therefore, would aim for APP transgene expression that mimics the endogenous APP gene. As an initial step in developing an animal model, we have identified a 4.5 kb DNA fragment from the 5' end of the human APP gene, which mediates neuron-specific gene expression in the CNS of transgenic mice, using E. coli lacZ as a reporter gene. Detectable levels of transgene expression are found in most neurons but not in glial and vascular endothelial cells. The expression pattern of this reporter gene closely resembles the distribution of endogenous APP mRNA in both the human and mouse CNS.     

The 21st century epidemic: infections as inductors of neuro-degeneration associated with Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease’s pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive iper-activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances. Age-associated immune dis-functions induced by chronic sub-clinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline.Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contributing to increased cognitive impairment in preclinical and clinical AD.     

Bioenergetic Mechanisms in Astrocytes May Contribute to Amyloid Plaque Deposition and Toxicity

Alzheimer disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss, and deposition of amyloid β (Aβ) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Aβ cytotoxicity, which may, in part, be related to their greater reliance on glycolytic metabolism. Here we show that, in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), results in increased accumulation of Aβ within and around astrocytes and greater vulnerability of these cells to Aβ toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that overexpress human Aβ. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein expression in astrocytes that paralleled the escalation of the Aβ plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, although at a later age (9 months) than GFAP and Aβ. Immunohistochemical staining showed significant reactive astrogliosis surrounding Aβ plaques with increased PFKFB3 activity in 12-month-old TgCRND8 mice, an age when AD pathology and behavioral deficits are fully manifested. These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology.     

EGb 761 is a neuroprotective agent against beta-amyloid toxicity.

Beta-amyloid (Abeta) deposition likely plays a causal role in the lesions that occur in Alzheimer's disease (AD). The Ginkgo biloba extract EGb 761 is widely prescribed in the treatment of cognitive deficits that are associated with normal and pathological brain aging such as AD. We have investigated here the potential effectiveness of EGb 761 against cell death produced by Abeta fragments on primary cultures of hippocampal cells, these cells being severely damaged in AD. A co-treatment with EGb 761 protected cells against toxicity induced by Abeta fragments in a concentration dependent manner. The effect of EGb 761 was even significant if added up to 8 hr to cells and was shared by its flavonoid fraction CP 205, whereas the terpenes bilobalide and ginkgolide B were ineffective. EGb 761 also displayed protective effects against toxicity produced by either H2O2 or nitric oxide, two neurotoxic agents that possibly mediate Abeta toxicity. Moreover, EGb 761, and to a lesser extent CP 205, completely blocked Abeta-induced events, such as reactive oxygen species accumulation and apoptosis. Taken together, these results and those obtained by other groups highlight the neuroprotective abilities of EGb 761 against dysfunction and death of neurons caused by Abeta deposits.     

Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging

Alzheimer disease (AD) is a neurodegenerative disease clinically characterized by progressive cognitive dysfunction. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by reactive oxygen species is prominent in AD, and several reports suggest the relationship between a change in redox status and AD pathology containing progressive Aβ deposition, the activation of glial cells, and mitochondrial dysfunction. Therefore, we performed immunohistochemical analysis using a transgenic mouse model of AD (APdE9) and evaluated the activity of superoxide dismutase in brain tissue homogenates of APdE9 mice in vitro. Together with those analyses, in vivo changes in redox status with age in both wild-type (WT) and APdE9 mouse brains were measured noninvasively by three-dimensional electron paramagnetic resonance (EPR) imaging using nitroxide (3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy) as a redox-sensitive probe. Both methods found similar changes in redox status with age, and in particular a significant change in redox status in the hippocampus was observed noninvasively by EPR imaging between APdE9 mice and age-matched WT mice from 9 to 18 months of age. EPR imaging clearly visualized the accelerated change in redox status of APdE9 mouse brain compared with WT. The evaluation of the redox status in the brain of AD model rodents by EPR imaging should be useful for diagnostic study of AD.     

Neurovascular and Cognitive failure in Alzheimer’s Disease: Benefits of Cardiovascular Therapy

Alzheimer’s disease (AD) is a multifactorial and multifaceted disease for which we currently have very little to offer since there is no curative therapy, with only limited disease-modifying drugs. Recent studies in AD mouse models that recapitulate the amyloid-β (Aβ) pathology converge to demonstrate that it is possible to salvage cerebrovascular function with a variety of drugs and, particularly, therapies used to treat cardiovascular diseases such as hypercholesterolemia and hypertension. These drugs can reestablish dilatory function mediated by various endothelial and smooth muscle ion channels as well as nitric oxide availability, benefits that result in normalized brain perfusion. These cerebrovascular benefits would favor brain perfusion, which may help maintain neuronal function and, possibly, delay cognitive failure. However, restoring cerebrovascular function in AD mouse models was not necessarily accompanied by rescue of cognitive deficits related to spatial learning and memory. The results with cardiovascular therapies rather suggest that drugs originally designed to treat cardiovascular diseases that concurrently restore cerebrovascular and cognitive function do so through their pleiotropic effects. Specifically, recent findings suggest that these drugs act directly on brain cells and neuronal pathways involved in memory formation, hence, working simultaneously albeit independently on neuronal and vascular targets. These findings may help select medications for patients with cardiovascular diseases at risk of developing AD with increasing age. Further, they may identify molecular targets for recovering memory pathways that bear potential for new therapeutic avenues.