Strategy For Alzheimer's Disease Research Articles

Cognitive Intervention As an Early Non-pharmacological Strategy in Alzheimer's Disease: A Translational Perspective.

Brain amyloid-β (Aβ) accumulation is currently considered the main causative pathophysiological event in Alzheimer's disease (AD) (Hardy and Higgins, 1992; Karran et al., 2011). Importantly, this process is thought to precede the onset of AD clinical symptoms by more than two decades, indicating that early therapeutic strategies prior to symptomatology offer the best chance of success. In line with this, there is growing attention being paid to the concept of cognitive reserve (CR) (Stern et al., 1994; Stern, 2002). CR concept is based on extensive epidemiological data indicating that those with higher lifetime levels of social, physical, and cognitive engagement have a lower risk of developing dementia despite the presence of brain pathology (Fratiglioni et al., 2004; Nithianantharajah and Hannan, 2009). Recently, cognitive intervention (CI)—such as cognitive training (Bahar-Fuchs et al., 2013), cognitive stimulation (Woods et al., 2012), and cognitive rehabilitation (Clare et al., 2003)—has emerged as a potential non-pharmacological strategy for the treatment and prevention of AD (Gates and Sachdev, 2014). Although based upon distinct theoretical constructs, these CI strategies are frequently not distinguished in clinical trials.

Prevention is best strategy for Alzheimer's disease.

Most people with Alzheimer's disease have late onset disease in which genetic predisposition and environmental factors combine to contribute to its development.

Erratum: Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease.

Due to an oversight of the corresponding author, the list of authors was originally published incorrectly in the manuscript entitled "Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease", published in Current Alzheimer Research, volume 12, no. 4, 2015, pp. 298-313. Due to this oversight, the correct first author was omitted from the original byline. The correct list of authors, with the true first author, is provided below: Authors: Peter Cao, Nady Braidy, Martin Zarka, Jeffrey Welch and Wallace Bridge. Affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Syd-ney, Australia, NSW 2052.

Treatment strategies in Alzheimer's disease: a review with focus on selenium supplementation.

Alzheimer’s disease (AD) is a neurodegenerative disorder presenting one of the biggest healthcare challenges in developed countries. No effective treatment exists. In recent years the main focus of AD research has been on the amyloid hypothesis, which postulates that extracellular precipitates of beta amyloid (Aβ) derived from amyloid precursor protein (APP) are responsible for the cognitive impairment seen in AD. Treatment strategies have been to reduce Aβ production through inhibition of enzymes responsible for its formation, or to promote resolution of existing cerebral Aβ plaques. However, these approaches have failed to demonstrate significant cognitive improvements. Intracellular rather than extracellular events may be fundamental in AD pathogenesis. Selenate is a potent inhibitor of tau hyperphosphorylation, a critical step in the formation of neurofibrillary tangles. Some selenium (Se) compounds e.g. selenoprotein P also appear to protect APP against excessive copper and iron deposition. Selenoproteins show anti-inflammatory properties, and protect microtubules in the neuronal cytoskeleton. Optimal function of these selenoenzymes requires higher Se intake than what is common in Europe and also higher intake than traditionally recommended. Supplementary treatment with N-acetylcysteine increases levels of the antioxidative cofactor glutathione and can mediate adjuvant protection. The present review discusses the role of Se in AD treatment and suggests strategies for AD prevention by optimizing selenium intake, in accordance with the metal dysregulation hypothesis. This includes in particular secondary prevention by selenium supplementation to elderly with mild cognitive impairment.

Mechanical problem-solving strategies in Alzheimer's disease and semantic dementia.

The goal of this study was to explore whether the tool-use disorders observed in Alzheimer's disease (AD) and semantic dementia (SD) are of the same nature as those observed in left brain-damaged (LBD) patients. Recent evidence indicates that LBD patients with apraxia of tool use encounter difficulties in solving mechanical problems, characterized by the absence of specific strategies. This pattern may show the presence of impaired mechanical knowledge, critical for both familiar and novel tool use. So, we explored the strategies followed by AD and SD patients in mechanical problem-solving tasks in order to determine whether mechanical knowledge is also impaired in these patients. We used a mechanical problem-solving task in both choice (i.e., several tools were proposed) and no-choice (i.e., only 1 tool was proposed) conditions. We analyzed quantitative data and strategy profiles. AD patients but not SD patients met difficulties in solving mechanical problem-solving tasks. However, the key finding is that AD patients, despite their difficulties, showed strategy profiles that are similar to that of SD patients or controls. Moreover, AD patients exhibited a strategy profile distinct from the one previously observed in LBD patients. Those observations lead us to consider that difficulties met by AD patients to solve mechanical problems or even to use familiar tools may not be caused by mechanical knowledge impairment per se. In broad terms, what we call apraxia of tool use in AD is certainly not the same as apraxia of tool use observed in LBD patients. (PsycINFO Database Record

EVIDENCE SUPPORTING A THERAPEUTIC STRATEGY FOR ALZHEIMER'S DISEASE BY REMOVAL OF BLOOD AB: PATIENTS WHO HAVE UNDERGONE HEMODIALYSIS EXHIBIT LOWER AB DEPOSITION IN THE BRAIN

EVIDENCE SUPPORTING A THERAPEUTIC STRATEGY FOR ALZHEIMER'S DISEASE BY REMOVAL OF BLOOD AB: PATIENTS WHO HAVE UNDERGONE HEMODIALYSIS EXHIBIT LOWER AB DEPOSITION IN THE BRAIN

Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins?

Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD.

Multitarget Strategies in Alzheimer’S Disease: Benefits and Challenges on the Road to Therapeutics

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.

Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβ oligomers: Implications for novel therapeutic strategy in Alzheimer's disease

The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-β (Aβ) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrPC). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aβ oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aβ cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrPC null mice (as well as rat neurons in which PrPC expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aβ oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrPC. This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aβ. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD.

Does glimepiride provide a novel mechanism of neutralising toxic amyloid-β?

Alzheimer's disease is associated with the accumulation within the brain of amyloid-β (Aβ) peptides that damage synapses and affect memory. Our recent study examined Alzheimer’s-related neurodegeneration by incubating cultured neurons with Aβ and measuring synaptic density. We showed that glimepiride, a sulphonylurea used for the treatment of diabetes, protected neurons against Aβ-induced synapse damage by changing the responsiveness of neurons to Aβ. Although glimepiride-treated neurons bound similar amounts of Aβto control neurons less Aβaccumulated within lipid rafts. More specifically, glimepiride reduced the Aβ-inducedactivation of cytoplasmic phospholipase A 2 (cPLA 2 ), aberrant activation of which causes synapse damage. Glimepiride also reduced the Aβ-induced increase in cholesterol that was required for the activation of cPLA 2 suggesting that drug-induced modifications of membrane micro-environments alter the Aβ-induced signalling pathways that lead to synapse damage. Therapeutic strategies in Alzheimer’s disease often include neutralising toxic forms of Aβ. Although several monoclonal antibodies (mAbs) targeting Aβ are currently in clinical trials, there remain concerns over their side effects, their ability to cross the blood brain barrier and their effectiveness. Here we offer an alternative mechanism for neutralising Aβ. Glimepiride caused the release of soluble cellular prion proteins (PrP C ), a receptor for toxic forms of Aβ. The soluble PrP C bound to and neutralised Aβ thus preventing synapse damage. Such observations raise the possibility that glimepiride could induce soluble PrP C within the brain that will neutralise toxic Aβ, reduce synapse damage and hence delay the progression of cognitive decline in Alzheimer’s disease.

Sialic acid (SA)-modified selenium nanoparticles coated with B6 peptide for potential use in Alzheimer's disease

The blood–brain barrier (BBB) is a formidable gatekeeper toward exogenous substances, playing an important role in brain homeostasis and maintaining a healthy microenvironment for complex neuronal activities. However, it also greatly hinders drug permeability into the brain and limits the management of brain diseases. The development of new drugs that show improved transport across the BBB represents a promising strategy for Alzheimer's disease (AD) intervention. Whereas a previous study of receptor-mediated endogenous BBB transport systems has focused on a strategy of using transferrin to facilitate brain drug delivery system, a system that still suffers from limitations including synthesis procedure, stability and immunological response, in the present study, we synthetized sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with an alternative peptide-B6 peptide (B6-SA-SeNPs, a synthetic selenoprotein analogue), which shows high permeability across the BBB and has the potential to serve as a novel nanomedicine for disease modification in AD. Laser-scanning confocal microscopy, flow cytometry analysis and inductively coupled plasma-atomic emission spectroscopy ICP-AES revealed high cellular uptake of B6-SA-SeNPs by cerebral endothelial cells (bEnd.3). The transport efficiency of B6-SA-SeNPs was evaluated in a Transwell experiment based on in vitro BBB model. It provided direct evidence for B6SA-SeNPs crossing the BBB and being absorbed by PC12 cells. Moreover, inhibitory effects of B6-SA-SeNPs on amyloid-β peptide (Aβ) fibrillation could be demonstrated in PC12 cells and bEnd3 cells. B6-SA-SeNPs could not only effectively inhibit Aβ aggregation but could disaggregate preformed Aβ fibrils into non-toxic amorphous oligomers. These results suggested that B6SA-SeNPs might provide a promising platform, particularly for the application of nanoparticles in the treatment of brain diseases.

Mechanical problem-solving strategies in Alzheimer’s Disease and Semantic Dementia

Mechanical problem-solving strategies in Alzheimer’s Disease and Semantic Dementia

Novel strategies for Alzheimer's disease treatment: An overview of anti-amyloid beta monoclonal antibodies

Alzheimer's disease (AD) is a multifactorial, progressive neurodegenerative disorder with a poor prognosis, and thus, novel therapies for AD are certainly needed in a growing population of elderly patients or asymptomatic individuals, who are at risk for AD, worldwide. It has been established that some AD biomarkers such as amyloid-beta load in the brain, precede the onset of the disease, by approximately 20 years. Therefore, the therapy to prevent or effectively treat AD has to be initiated before the emergence of symptoms. A goal of this review is to present the results of recent clinical trials on monoclonal antibodies against amyloid beta, used for the treatment of AD and also to address some of the current challenges and emerging strategies to prevent AD. In recent trials, a monoclonal antibody, i.e. solanezumab has shown some beneficial cognitive effects among mild AD patients. Ongoing studies with gantenerumab and crenezumab will examine when exactly the AD treatment, aimed at modifying the disease course has to be started. This review was based on Medline database search for trials on passive anti-AD immunotherapy, for which the main timeframe was set from 2012 to 2015.

Cuba's Strategy for Alzheimer Disease and Dementia Syndromes.

Dementia is a great challenge to public health in Cuba due to its impact on society and families. Cuba's National Intervention Strategy for Alzheimer Disease and Dementia Syndromes is designed to address this challenge. The Strategy includes working guidelines for primary and secondary care, education about rights of people with cognitive impairment, professional development, research, and health promotion and dementia prevention. An associated action plan, focused on primary care, includes proposals for creation of memory clinics, day centers and comprehensive rehabilitation services for cognitive stimulation. Short-term measures proposed include increasing early detection; creating a dementia morbidity and mortality registry; promoting professional training; providing support for families; and promoting basic and clinical research on dementia. Medium-term proposals aim to reduce dementia incidence and mortality by controlling risk factors and promoting healthy lifestyles, offering new treatment options and optimizing early detection. A set of indicators has been developed to evaluate strategy implementation. With this strategy, Cuba joins the small number of developing countries that have responded to WHO's call to improve care for patients with dementia and alleviate its impact on society and families. KEYWORDS Dementia, Alzheimer disease, aging, national health programs, social stigma, primary prevention, health promotion, civil rights, Cuba.

Perspectives on Inhibiting β-Amyloid Aggregation through Structure-Based Drug Design.

Targeting β-amyloid (Aβ) remains the most desired strategy in Alzheimer's disease (AD) drug discovery research. Many peptides that specifically target Aβ aggregates are known, encompassing efforts from both industrial and academic research settings. However, in clinical terms, not much success has been gained with peptide research; in turn, small drug-like molecules are already globally recognized as showing promise as an alternate approach. Aβ aggregation inhibitors are the most important part of the multifunctional drug design regimen for treating AD. Unfortunately, rational drug design approaches with small molecules are still in the initial stages. Herein we highlight, update, and elaborate on the structural anatomy of Aβ and known Aβ aggregation inhibitors in hopes of helping to optimize their use in structure-based drug design approaches toward inhibitors with greater specificity. Furthermore, we present the first review of efforts to target a previously uncharacterized region of acetylcholinesterase: the N-terminal 7-20 sub-region, which was experimentally elucidated to participate in Aβ aggregation and deposition.

Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer's disease.

Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteine. However, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacy to elevate depleted GSH levels in several in vivo and in vitro models of disease. It has been suggested that the decline in GSH levels in AD, may be associated with down regulation of GSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor γ-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves as a crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH, and the administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD.

Antiepileptic drugs as a novel therapeutic strategy in Alzheimer's disease

Antiepileptic drugs as a novel therapeutic strategy in Alzheimer's disease

Imaging Vascular Disease and Amyloid in the Aging Brain: Implications for Treatment.

Vascular risk factors (e.g. hypertension, dyslipidemia and diabetes) are well known risk factors for Alzheimer' disease. These vascular risk factors lead to vascular brain injuries, which also increase the likelihood of dementia. The advent of amyloid PET imaging has helped establish that vascular risk factors also lead to Alzheimer's disease via pathways that are independent from vascular brain injuries, at least, when vascular brain injuries are measured as white matter lesions and infarcts. While vascular brain injuries (white matter lesions and infarcts) do not seem to influence amyloid pathology, some evidence from amyloid imaging suggests that increased vascular risk is related to increased amyloid burden. Furthermore, while vascular brain injuries and amyloid have an additive and independent impact on brain integrity, vascular risk factors might potentiate the impact of amyloid on cortical thickness on brain regions vulnerable to Alzheimer's disease. New research should further explore and confirm, or refute, possible interactions between amyloid and vascular risk factors on brain integrity and cognition. Neuroimaging tools used to assess vascular brain integrity should also be expanded. Measuring cortical blood flow or damage to the capillary system might, for instance, give insight about how vascular risk factors can be associated to amyloid burden and impact. These findings also stress the need for monitoring vascular risk factors in midlife as a strategy for Alzheimer's disease prevention.

Discourse intervention strategies in Alzheimer's disease: Eye-tracking and the effect of visual cues in conversation

ObjectiveThe goal of this study was to investigate whether on-topic visual cues can serve as aids for the maintenance of discourse coherence and informativeness in autobiographical narratives of persons with Alzheimer's disease (AD).MethodsThe experiment consisted of three randomized conversation conditions: one without prompts, showing a blank computer screen; an on-topic condition, showing a picture and a sentence about the conversation; and an off-topic condition, showing a picture and a sentence which were unrelated to the conversation. Speech was recorded while visual attention was examined using eye tracking to measure how long participants looked at cues and the face of the listener.ResultsResults suggest that interventions using visual cues in the form of images and written information are useful to improve discourse informativeness in AD.ConclusionThis study demonstrated the potential of using images and short written messages as means of compensating for the cognitive deficits which underlie uninformative discourse in AD. Future studies should further investigate the efficacy of language interventions based in the use of these compensation strategies for AD patients and their family members and friends.

Region- and age-dependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer's disease

To characterize the mechanisms underlying region- and age-dependent hippocampal synaptic dysfunction in Alzheimer's disease, we used transgenic CRND8 mice, expressing the Swedish-Indiana APP mutation. In 2-month-old mice, no β-amyloid plaques deposition, but the presence of soluble oligomers, were found in CA1 area but not in dentate gyrus (DG). At this age, long-term potentiation (LTP) was reduced selectively in CA1. In 6-month-old mice, the presence of soluble oligomers was accompanied by accumulation of β-amyloid plaques and decreased LTP in CA1 and DG regions. In both regions, the loss of LTP was linked to reduced N-methyl-D-aspartate (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) current ratio. The acetylcholine-esterase inhibitor, neostigmine rescued LTP in CA1 area at early stage of the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects were associated with a normalization of the NMDA to AMPA ratio. The association between the recovery of LTP and the normalization of the NMDA to AMPA ratio provides information on new possible therapeutic strategies in Alzheimer's disease.