Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies


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Such a notion is further supported by the finding that fibroblasts from AD patients demonstrated abnormal mitochondrial dynamics compared to normal healthy fibroblasts from age-matched control patients Wang et al. Increased mitochondrial ROS production: Along with the abnormalities in oxidative energy metabolism, there is also evidence of oxidative stress in AD brain. This is manifested by increased protein oxidation, lipid peroxidation , nucleic acid oxidation and glycooxidation Butterfield et al. It is unclear whether the accumulation of ROS is a precursor or a consequence of other cellular dysfunctions.

The sources of ROS-mediated damage appear to be multi-faceted in AD, with interactions between abnormal mitochondria, redox transition metals and other factors Galindo et al. Activation of mitochondrial-mediated apoptotic pathway: Mitochondria play a pivotal role in life and death of cells and likely contribute importantly to the initiation or progression of AD Picklo and Montine, Extensive studies have suggested that increased permeabilization of the mitochondrial membrane with subsequent release of cytochrome c is a key initiative step in the apoptotic process Gogvadze et al.

Two mechanisms have been proposed to explain the MMP: the formation of a mitochondrial Permeability Transition Pore mPTP and the insertion of Bcl-2 family members at the mitochondrial membrane Galindo et al. As regard the first mechanism, it has been observed that the mPTP is composed of 3 main components. These include voltage-dependent anion channel in the outer membrane, adenine nucleotide translocase protein in the inner membrane and cyclophilin D cypD protein in the matrix Halestrap et al.

Second mechanism related to the Bcl-2 family of proteins, is still under investigations. The full manner in which it modulates the changes in membrane permeability remains unknown. Loss of basal forebrain cholinergic neurons and synaptic loss: Li and Shen reported that one of the major characteristics of AD is the degeneration of basal forehead cholinergic neurons.

Clinical evidence obtained from AD patients has shown a specific reduction in choline acetyltransferase, acetylcholine esterase activities in biopsied brain tissue and a loss of cholinergic neurons indicating the involvement of the forebrain cholinergic system in AD Klafki et al.

Numerous experimental studies have demonstrated that lesions of the basal forebrain cholinergic system result in significant learning and memory impairment thus indicate the important role of the cholinergic system in learning and memory processing Li and Shen, ; Schaeffer et al. There are two major cholinergic systems existing in the basal forebrain: One derives from the nucleus basalis magnocellularis which projects primarily to the cerebral cortex, the other derives from the medial septum which projects primarily to the hippocampus.

Lesions in these two pathways have been shown to produce significant memory deficits Li and Shen, Synaptic loss is the most robust correlate of AD associated with cognitive deficits Lambert et al. Pleckaityte reported the existence of fibrillar intermediates called protofibrils PFs. PFs are the structural intermediates to fully fledged fibrils and they are neurologically active. Current available medications that have passed FDA approval for the treatment of AD include acetylcholine esterase inhibitors for mild to moderate cases and Memantine, an N-methyl-D- aspartate receptor antagonist for the treatment of moderate to severe Alzheimer dementia.

All these drugs produce only modest symptomatic improvements in some of the patients. Therefore, there is a great need for development of therapeutic strategies with disease modifying effects based on the underlying pathogenetic cascade of events that characterize AD Salloway and Correia, ; Klafki et al. In this review, we will discuss both symptomatic and disease modifying approaches looking forward for complete cure of AD.

The hypothesis is supported by evidence that drugs that potentiate central cholinergic function have some value in symptomatic treatment during early stages of the disease Trinh et al. M 1 muscarinic acetylcholine-receptor agonists were suggested to be potentially useful not only for symptomatic treatment of AD but to a limited extent also for causal therapy Fisher, ; Fisher et al. In the last decade, the Food and Drug Administration in the United States approved four drugs for the treatment of AD: tacrine, donepezil, rivastigmine and most recently, galantamine.

All four drugs inhibit acetylcholinesterase, the degradative enzyme for acetylcholine, thereby increasing the duration of action of acetylcholine. These medications are associated with modest, symptomatic improvement for some patients with AD Doody et al. They tend to stabilize memory during the first year of treatment and make the subsequent decline more gradual Salloway and Correia, However, it has been reported that, although the cholinesterase inhibitors improve cognitive and global function in many patients, but their efficacy wanes over time Saunders, ; Walker et al.

Recently, Malek et al. GH and in some extents IGF-1 affects most of the major neurotransmitters differently in several brain regions, including the noradrenergic, dopaminergic, glutaminergic at least at the receptor level , opioidergic and cholinergic systems. GH may be useful in the treatment of men.

Surely, this usefulness needs more and deep human studies. Memantine, currently the only symptomatic treatment approved for moderate to severe AD, protects against the neurodegenerative effects of the excitatory neurotransmitter glutamate Jacobsen et al. It has also been reported that it may provide symptomatic improvement through effects on the functions of hippocampal neurons Reisberg et al.

A combination therapy over 6 months with memantine plus donepezil choline esterase inhibitor in patients with moderate to severe AD significantly improved cognition, activities of daily living and behavior compared with placebo Tariot et al. The durability of clinical improvements associated with memantine treatment is not known.

Behavioral problems are often the most disturbing symptoms in dementia, often leading to higher levels of care. Apathy is the most common behavioral symptom in Alzheimer disease, increasing with disease severity. There is no approved treatment for these apathetic symptoms till now. Depression and irritability are common and may respond well to low doses of serotonin reuptake inhibitors Salloway and Correia, Recent studies have raised concern about the safety and efficacy of atypical neuroleptics in patients with dementia and suggest that these drugs be used with careful monitoring Schneider et al.

However, the majority of these agents are not specific for the secretase cleavage of APP. This, in turn, may prevent the cleavage and processing of additional substrates, which could result in various adverse effects Evin et al. It has been reported that Notch-deficient knock-out mice exhibit reduced hippocampal neuroplasticity, neurodegeneration and impaired memory Saura et al. Another concern is that chronic inhibition, in animal models, is associated with effects in the gastrointestinal system, thymus and spleen Neugroschl and Sano, Tramiprosate is a glycosaminoglycan GAG mimetic that is in clinical trial testing.

Despite these disappointing results, the investigational drug progressed into a phase III trial in Northern America, which was recently declared by the FDA to have failed. Immunotherapy: A novel and controversial approach to treat AD is based on vaccine therapy. All these changes were accompanied by improved learning. This failed trial has led researchers to develop more selective and advanced immunotherapies White et al.

Statins: Epidemiologic evidence suggests that statins may reduce the risk of developing AD Jick et al. The mechanism of this putative protective effect is not completely understood, but may be related to the relationship between elevated cholesterol and amyloid deposition Golde, The involvement of apolipoprotein E, an established AD risk factor, in cholesterol metabolism provides support for this hypothesis Silvestrelli et al.

Advanced glycation end products: Advanced Glycation End products AGEs are formed endogenously during glycation and can also be ingested in a variety of foods Vlassara et al. These AGEs have been implicated in aging through a variety of mechanisms, including increased protein cross linking and increased free radical formation and as proinflammatory mediators. Receptor for AGEs is an immunoglobulin supergene family expressed on the cell surface of multiple cell types throughout the brain and on the blood brain barrier.

In AD, this receptor is up-regulated on cells in the hippocampus, such as astrocytes and microglia Sasaki et al. Amyloid is known to bind to this receptor. This may be one way in which the inflammatory cascade is stimulated and thus may lead to cell death. Preclinical studies have suggested that blocking this receptor against amyloid binding protects the cell by decreasing plaque formation and inflammation and it may have an effect on memory functioning Chen et al.

Clinical studies are still ongoing. Peroxisome proliferator-activated receptor-gamma agonists: The peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and pioglitazone, have been assessed as potential anti-amyloid disease-modifying treatments in recently reported phase II trials of patients with AD.

Clinical trials in diabetic and non-diabetic patients with AD are still under investigations. Erythropoeitin derivatives: Erythropoeitin EPO , a well-established hematopoietic factor, possesses generalized neuroprotective and neurotrophic properties. Increased expression of EPO receptors in the brains of AD patients support a role for EPO derivatives in this prototype of neurodegenerative disorders. Protection by EPO derivatives against beta amyloid toxicity in cultured neurons have also been documented. Slight improvements in functional outcome indeed have been reported in models of Parkinson disease and amyotrophic lateral sclerosis Siren et al.

Therefore, another potential therapeutic avenue has been directed towards the alternate hypothesis regarding the pathophysiology of AD which is the hyperphosphorylation of Tau proteins. Other neuroprotective strategies could also be targeted towards varieties of secondary mechanisms such as oxidative injury and lipid peroxidation of cell membranes Yaari and Corey-Bloom, , inflammation Metcalfe and Figueiredo-Pereira, and alteration of metal ion homeostasis Crouch et al.

Therapeutic approaches directed against tau protein include Inhibitors of tau kinases Sun et al. These kinases are involved in the phosphorylation of Tau protein. They include: glycogen synthase kinase 3, cyclin-dependent protein kinase-5, casein kinase-1, protein kinase A, protein kinase C, calcium and calmodulin-dependent protein kinase-II, microtubule-affinity regulation kinase and mitogen activated protein kinase family members Biran et al.

These proteins have been suggested as therapeutic targets for AD. However, this approach is hindered due to the ubiquitous expression of these kinases, their pleiotropic activities in countless cellular functions and the low selectivity of inhibitors for specific kinases Churcher, ; Stoothoff and Johnson, Therefore, the development of Tau aggregation inhibitors that would also be able to disaggregate filaments could provide an alternative to existing pharmaceutics strategies Bulic et al.

The inhibitory effect of those compounds could take place on different levels, for example, interference with a particular Tau conformation, association of dimers or oligomers, elongation of filaments and so on. In particular, this compound could interfere with the initial generation of nuclei or with the further elongation of fibrils.

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Alzheimer Disease: Advances in Pathogenesis, Diagnosis, and Therapy

This could be achieved by tight binding of the compound to the protein monomer or oligomer. Other therapeutic includes the steric obstruction of the protein-protein interaction by the compound or interference with the polyanion inducers of aggregation Pickhart et al. Neuroprotective approaches targeting secondary mechanisms Antioxidants: Antioxidant molecules are capable of neutralizing free or incorrectly bound metals, thereby interfering with the 'down-stream' generation of ROS and other radicals.

Therefore, antioxidants may be used mainly as a preventive approach Behl and Moosmann, Anti-inflammatory drugs: Markers of neuroinflammation including activated microglia and astrocytes, complement components and inflammatory cytokines are typically observed in association with AD neuropathology Tuppo and Arias, Observational retrospective and prospective studies indicated that the long-term use of non steroidal anti-inflammatory NSAIDs may have a preventive effect against the development of AD suggesting that neuroinflammation may contribute to the neurodegeneration Szekely et al.

In APP-transgenic mice, ibuprofen reduced amyloid load and microglial activation Lim et al. The selective cyclooxygenase COX -2 inhibitor rofecoxib and the non-selective NSAID, naproxen, were also tested in a clinical randomized control trial for the treatment of mild to moderate AD. However, neither drug was able to slow the rate of cognitive decline as compared with the placebo control group Aisen et al. Later on, El-Sayed et al. Therapeutic approaches targeting alteration of metal ion homeostasis: Other than the amyloid cascade hypothesis of AD, alteration of metal ion homeostasis plays also a critical role in AD pathogenesis.

It was found that NFTs may in some way be involved in, or regulated by, metal metabolism. The latter has an increased affinity for the phospholipid heads of the membrane bilayer Lau et al. The resulting radicals induce oxidative stress damage of lipids, proteins and DNA, ultimately leading to synaptic and neuronal loss Bush, , ; Barnham et al.

Accordingly, modulation of metal ions has been proposed as a disease-modifying therapeutic strategy for AD Crouch et al. Antioxidants and metal-modulators such as metal chelators, metal complexes, metal-protein attenuating compounds, represent such therapeutic strategies. Neuronal regeneration approaches: There are no effective interventions till now that significantly forestall or reverse neurodegeneration and cognitive decline in AD.

In the past decade, the generation of new neurons has been recognized to continue throughout adult life in the brain's neurogenic zones. A major challenge has been to find ways to harness the potential of the brain's own neural stem cells to repair or replace injured and dying neurons. In the past five years it has become evident that Bone Marrow BM houses more 'primitive', multipotent stem cells that are capable of giving rise to tissues of all embryonic germ layers. BM-derived cells have been shown by independent investigators to give rise to neural cells in vitro. In addition, in vivo studies showed that BM cells migrate into the brain where they appear to differentiate into neurons and glia.

The mechanism for transdifferentiation of BM to neural cells is not clear and may reflect the capacity of BM-derived cells to fuse with injured neurons Wu et al. The administration of Hematopoietic Growth Factors HGF or cytokines has been shown to promote brain repair by a number of mechanisms, including increased neurogenesis, anti-apoptosis and increased mobilization of bone marrow-derived microglia into brain. In this light, cytokine treatments may provide a new therapeutic approach for many brain disorders, including neurodegenerative diseases like AD.

In addition, neuronal hematopoietic growth factor receptors provide novel targets for the discovery of peptide-mimetic drugs that can forestall or reverse the pathological progression of AD Sanchez-Ramos et al. The application of HGF for the treatment of AD has not yet been undertaken but there is a strong rationale for initiating clinical studies.

In this review we tried to cover briefly the different aspects of AD, its cause, pathophysiological changes, clinical picture and treatment. AD is an irreversible progressive neurodegenerative disease that slowly destroys memory and thinking skills. Many risk factors are associated with the development of the disease; the accuracy of its diagnosis is a problem inherent to all studies of this disease. This co-elevated inflammation and amyloidogenesis resulted in neuronal cell death and thus memory impairment.

There is hope that in the coming future, improved treatments and diagnostic methods will soon be available and will be of great help to minimize the occurrence of the disease and treat its patients. Subscribe Today. Science Alert. All Rights Reserved. Review Article. Similar Articles in this Journal. Search in Google Scholar. Pakistan Journal of Biological Sciences, DOI: Adlard, P. Bush, Metals and Alzheimer's disease. Alzheimers Dis. Saumier, R. Briand, J. Laurin, F. Gervais, P. Tremblay and D. Garceau, Schafer, M. Grundman, E. Pfeiffer and M. Sano et al.

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Di Lisa and M. Forte, The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. Masters, K. Barnham, A. Bush and P. Adlard, Pharmacotherapeutic targets in Alzheimers disease. Cell Mol. Sjogren, B. Winblad and J. Pei, Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells. Neuroreport, Pickhart, I.

Khlistunova, J. Biernat, E. Mandelkow, E. Mandelkow and H. Waldmann, Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Tanzi, Therapeutics for Alzheimers disease based on the metal hypothesis. Neurotherapeutics, 5: Metals and neuroscience. Metal complexing agents as therapies for Alzheimers disease. Aging, The metallobiology of Alzheimers disease. Trends Neurosci. Perluigi and R.

Sultana, Oxidative stress in Alzheimers disease brain: New insights from redox proteomics. Masliah, R. Barbour, H. Grajeda and R. Motter et al. Mitochondrial fusion and fission in mammals. Yan, Walker, A. Schmidt, O. Arancio, L. Lue and S. Tau therapeutic strategies for the treatment of Alzheimers disease. Tew, C. Curtain, D. Smith and D. Carrington et al. Federoff and R. Kurlan, A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology, White and A. The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimers disease.

Protein phosphorylation and APP metabolism. Velasco, M. Lambert, K. Viola, S. Fernandez, S. Ferreira and W. Klein, Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. Bilobalide and neuroprotection. Stevens, C. Beck, R. Dubinsky and J. Kaye et al. Practice parameter: Management of dementia an evidence-based review. Report of the quality standards subcommittee of the American academy of neurology.

Guo, F. Fang, D. Chen and A. Sosunov et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimers disease. Kassem and O. Heikal, Promising therapy for Alzheimers disease targeting angiotensin converting enzyme and the cyclooxygense-2 isoform. Evans, P. Persinger, Erythropoietin and mild traumatic brain injury: Neuroprotective potential and dangerous side-effects.

Sernee and C. Masters, Inhibition of gamma-secretase as a therapeutic intervention for Alzheimers disease: Prospects, limitations and strategies. CNS Drugs, Gomez-Isla, B. Puig, M. Freixes, E. Ribe, E.

New Approaches to Alzheimer’s Diseases - Verna Porter, MD - UCLAMDCHAT

Dalfo and J. Avila, Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimers disease and tauopathies. Alzheimer Res. Glockshuber, Amyloid-beta aggregation. Therapeutic strategies in Alzheimers disease: M1 muscarinic agonists. Japan J. Michaelson, R. Brandeis, R. Haring, S. Chapman and Z. Pittel, M1 muscarinic agonists as potential disease-modifying agents in Alzheimers disease: Rationale and perspectives.

Ikuta, X. Zhu, G. Casadesus and J. Jordan, Mitochondrial biology in Alzheimers disease pathogenesis. Sahoo, S. Kaushalya, R. Desai and S. Maiti, Gurbindo and J. Laurin, Safety, tolerability and pharmacokinetic profile of Alzhemed, An anti-amyloid agent for Alzheimer's disease, in healthy subjects.

Geerts, H. NC Neurochem. Drugs, 5: Chalifour, D. Garceau, X. Kong and J. Laurin et al. Glycosaminoglycan mimetics: A therapeutic approach to cerebral amyloid angiopathy. Amyloid, 8: Structural classification of toxic amyloid oligomers. Saijo, B. Winner, M. Marchetto and F. Gage, Mechanisms underlying inflammation in neurodegeneration. Cell, Orrenius and B. Zhivotovsky, Multiple pathways of cytochrome c release from mitochondria in apoptosis. Acta Bioenergetics, Alzheimer disease therapy: Can the amyloid cascade be halted? Chang, K.

Viola, P. Lacor and M. Lambert et al. Zhao, J. Fei and W. Schwarz, Neuroscience, Selkoe, McStay and S. Clarke, The permeability transition pore complex: Another view. Biochimie, Scherping, S. Drose, U. Brandt and W. Muller et al. Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice. Need, K. Hayden, O. Chiba-Falek and A. Roses et al. Genome-wide scan of copy number variation in late-onset Alzheimers disease. Sastre, L. Dumitrescu-Ozimek, A. Hanke and I. Dewachter et al. Brain, Aliev, A. Nunomura, H.

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Jick, S. Seshardi and D. Drachman, Statins and the risk of dementia. Kovacs, Mitochondria and neuronal activity. Slowikowski, D. Westaway and H. Mount, Psychiatry Neurosci. Yassin, Role of erythropoeitin in prevention of chemotherapy-induced peripheral neuropathy. Staufenbiel, J. Kornhuber and J. Wiltfang, Therapeutic approaches to Alzheimers disease. Fink Eds. Springer, New York, pp: Lacor, P. Buniel, L. Chang, S. Fernandez and Y. Gong et al. Velasco, L. Viola and S. Fernandez et al. Ambroggio, D. Tew, R. Cappai and C. Masters et al. Koh, L. Kotilinek, R.

Kayed and C. Glabe et al. Nature, Shen, Selective loss of basal forebrain cholinergic neurons in APP transgenic mice. Yang, T. Chu, P. Chen and W. Beech et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. Laurin, R. Verreault, R. Hebert, B. The structure and function of microtubules are impaired as a consequence of the abnormal hyperphosphorylation of Tau protein, which precludes its ability to stabilize the monomers of alpha- and beta-tubulin Therefore, the interruption and reversal of this process may restore microtubular structure and function Moreover, GSK-3 inhibition downregulates the amyloidogenic cleavage of APP, which provides further evidence of the cross-talk between these two major pathological cascades in AD The recognition of core and secondary pathophysiological mechanisms in AD has led to the identification of molecular targets for the development of specific drugs.

Alzheimers Disease Targets For New Clinical Diagnostic And Therapeutic Strategies

In fact, more than pharmaceutical compounds are currently undergoing phase 2 and 3 trials These compounds can be grossly divided into anti-amyloid agents and drugs that target other pathological pathways. Studies involving stem-cell and gene therapy are also under way, but at more incipient stages of experimental validation. Red arrows indicate possible interventional targets with respective agent.

Overall pharmacologic treatments other than anti-amyloid therapy under research for Alzheimer's disease 11 , 32 , Intracerebral amyloidosis may start in the brain of individuals with AD many years before the onset of clinical symptoms 37 , Evidence of this pathological process can be depicted at prodromal or even at preclinical stages of the disease by the analysis of cerebrospinal fluid CSF and molecular neuroimaging biomarkers 37 , 38 , However, there is evidence that these interventions must be implemented at earlier stages of the disease process, i. It is accepted that two thirds of individuals with MCI may have intracerebral amyloid burden comparable with those with clinically manifested AD, indicating that intracerebral amyloidosis is an early event in the natural history of the disease 43 , This strategy is supposedly not associated with a significant risk of eliciting T-cell inflammatory reactions As occurred with active immunotherapy, successful preclinical studies with passive immunotherapy were followed by phase 1 and phase 2 trials for AD.

Afterward, advantageous results with transgenic animal models encouraged several centers to design clinical trials in order to establish effective treatments for AD patients and to change the disease course. Currently, some passive immunotherapies are being developed. A challengeable aspect concerns the efficacy against pathophysiology of the disease with avoidance of undesired side effects such as microhaemorrhage, vasogenic oedema, encephalitis, or neuroimaging abnormalities Across the screening cohorts enrolling placebo-treated patients, rarely occurrences of brain areas of microhaemorrhage have been described 49 , Conversely, another group reported vasogenic oedema with this drug Several passive immunotherapeutic agents have been evaluated by RCTs over the past years, namely bapineuzumab, solanezumab, gantenerumab, ponezumab, and crenezumab.

In phase 2 studies, this compound was examined in a randomized placebo controlled trial to determine dose, safety, and efficacy in patients with mild to moderate AD. Patients were given six infusions, in 13 distinct weeks, with last evaluation at week 78 Reversible and asymptomatic or transient vasogenic oedema was detected in 9. Recently, during The European Federation of Neurological Societies annual meeting, in Stockholm, Sweden , researchers reported that bapineuzumab failed to protect against cognitive and functional decline of AD patients undergoing a phase 3 trial Rare occurrences of micro-haemorrhage and vasogenic oedema have also been described with this drug 28 , However, subsequent phase 2 studies did not confirm clinical efficacy, and development of ponezumab for mild to moderate AD was interrupted However, it is yet to be determined whether treatment with this antibody can slow disease progression and improve clinical outcomes Other anti-amyloid strategies have been addressed by clinical trials.

Recently, semagacestat, a non-selective gamma-secretase inhibitor, has been examined as a potential treatment for AD patients Unfortunately, preliminary results from two ongoing long-term phase III trials found no efficacy. The studies were interrupted because researchers verified it did not slow disease progression and, in addition, was associated with increasing cognitive impairment and worsening daily living activities, as well with increasing risk for skin cancer with semagacestat Although vasogenic oedema has been a rare vascular event, a report described exacerbation of psoriatic skin lesions with this drug 21 , Avagacestat has been considered as a potently inhibitor of Ab40 and Ab42 formation, with selectivity for effects on APP relative to Notch proteins which interfere with cell proliferation, differentiation, and apoptosis.

In a study enrolling healthy subjects, this compound exerted a potent selective gamma-secretase inhibition with decreased CSF Ab levels, as well as the inhibition of the human Notch proteins The authors reported a good tolerability profile and no changes in histopathology of skin or in lymphocytes following 28 days of dosing, although this period was not enough to confirm such clinical alterations in humans However, the authors demonstrated no signicant reduction in these biomarkers, although they reported an acceptable safety and tolerability with this drug Another study was designed to compare chronic treatment of transgenic mice models of AD between the nonsteroidal anti-inflammatory CHF and a prototypal gamma-secretase inhibitor DAPT The authors observed that the CHF compound has effectively prevented amyloid accumulation in the brain tissue and behavioural impairment; however, no significant effects were found with DAPT treatment.

The inhibition of beta-secretase is another potential mechanism of disease modification in AD, given the major role of this enzyme in the amyloidogenic cleavage of the amyloid precursor protein APP. However, the inhibitory mechanism of this compound are not clear, and the reduction of amyloid-beta has been considered modest with low selectivity over other enzymes Using an AD transgenic mouse model, the immunogenicity and efficacy of the compound AF was tested and it was found that this active vaccine induced cellular and humoral immune responses against beta-amyloid pathophysiology in the brain tissue of the animals, without inducing microglial activation However, large clinical trials are needed to test this and other promising drugs.

These radiological findings are associated with cerebral amyloid angiopathy-related inflammation CAA-ri , and can be asymptomatic or present clinically with acute or sub-acute manifestations such as headache, seizures, focal neurological deficits, and behavioural disturbances 57 , Given its critical role in pathogenesis of AD, drug development may also target the production, processing phosphorylation and aggregation of Tau protein Two widely used mood stabilizers, lithium and valproate, are also inhibitors of this enzyme, reducing tau phosphorylation in animal models Proteomic studies in AD patients treated with valproate indicated ten differentially expressed proteins related to functional classes implicated in the neurobiology of the disease and to the therapeutic action of drug However, in a multicenter clinical trial conducted by the Alzheimer's Disease Cooperative Study ADCS , an accelerated decrease in total brain and hippocampal volume was observed after 1 year of followup among patients treated with divalproex sodium, which was accompanied by greater cognitive impairment In addition, valproate treatment of moderately demented AD patients did not delay the emergence of neuropsychiatric symptoms of agitation or psychosis, and was not associated with reduction of cognitive or functional decline; rather, it was associated with adverse effects such as somnolence, gait disturbance, tremor, diarrhoea and weakness Epidemiologic studies showed a reduced risk of developing dementia among patients with bipolar disorder treated chronically with lithium 71 , 72 , but there is limited evidence of the clinical benefits of lithium treatment for patients with or at risk for AD 73 , 74 , 75 , In a recent single-centre, placebo-controlled trial conducted in a sample of patients with amnestic MCI, long-term lithium treatment was associated with stabilization of cognitive and functional parameters, in addition to a reduction in CSF concentrations of phosphorylated Tau In a previous phase 2 study in patients with mild AD treated with lithium for a shorter 10 wk period, no significant differences were observed in biological GSK-3 activity and CSF biomarkers or clinical cognitive and functional outcomes In addition to that, the safety limits of chronic lithium treatment for older adults need to be determined, given the risk of renal impairment, hypothyroidism and other metabolic adverse effects Methylthioninium chloride known as Rember , also known as methylene-blue, is a phenothiazine widely used as a histological stain.

Currently, it is a promising compound being evaluated in AD trials. A phase 2b randomized trial of Rember monotherapy in mild and moderate AD patients suggested cognitive benefits in volunteers Results of a phase 3 trial are soon expected to assure its safety profile and efficacy as a disease-modifying drug for AD To date, treatment of AD relies on the symptomatic effects of cholinesterase inhibitors and NMDA-receptor antagonists.

Many promising compounds have been validated by experimental models as candidate disease-modifying drugs for AD; however, only a few of these appear in the pipeline of drug development, or have been clinically tested by RCTs. Overall results from these trials have so far been negative. Most phase 3 trials with candidate drugs for AD in the last decade failed to present unequivocal clinical benefits, or were suspended due to severe adverse events.

Likewise, results of ongoing phase 2 trials are discrete at most. This rather pessimistic scenario must be weighed against the huge financial costs of the transition from phase 2 to phase 3 trials, and further translation of this knowledge into clinical practice.


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Several issues must be addressed in future studies with candidate drugs in order to yield clinically relevant results, and support their generalization for the treatment of the massive population of patients with and at risk for AD. One critical issue refers to the stage of the disease in which one given treatment is prone to deliver clinically relevant benefits. The majority of studies with candidate disease-modifying drugs for AD recruited patients with clinically manifested dementia, when it may be too late to grant clinical benefits from the modification of the pathological process.

In other words, by treating demented patients with such drugs it may be possible to prove the concept of disease modification, but this effect may not be translated into significant changes to the natural course of the disease. Forthcoming trials should rather target disease modification in patients with very mild clinical symptoms such as incipient dementia or amnestic MCI , i. With respect to trials in MCI, it is essential to improve the definition of cases, i.

For this purpose, recruitment of patients for future studies should be rationally based on new diagnostic technologies including biochemical and imaging biomarkers e. Another important point refers to the duration of trials, and the best moment to start the intervention, given the long period of time prior to the onset of symptoms in which the pathological changes are evolving within the brain.

In other words, it is imperative to develop a better understanding of the disease process and the possibilities of modification of the AD pathogenesis, which requires evidence-based answers for the following three questions: who should be treated; when to start; and for how long? Finally, one should better define the outcomes of these trials, with biological measures to prove that the drug is efficacious in disease-modification even in the absence of significant clinical improvement.

Therefore, the notion of prevention of dementia in at-risk individuals must be reinforced. National Center for Biotechnology Information , U. Indian J Med Res. Orestes V. Author information Article notes Copyright and License information Disclaimer. Reprint requests : Dr Orestes V.

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Received May This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC. Abstract Alzheimer's disease AD is a progressive and irreversible neurodegenerative disease, and corresponds to the most common cause of dementia worldwide. Keywords: Alzheimer's disease, antidementia drug, beta-amyloid, cognitive impairment, Tau, treatment.

Introduction Alzheimer's disease AD is the leading cause of dementia worldwide, affecting more than half of the overall number of demented individuals, which has been estimated to be around 24 million across all nations 1. Open in a separate window. Therapeutic targets for disease modification in AD The recognition of core and secondary pathophysiological mechanisms in AD has led to the identification of molecular targets for the development of specific drugs.

Table I Compounds targeted to anti-beta-amyloid treatment. Table II Overall pharmacologic treatments other than anti-amyloid therapy under research for Alzheimer's disease 11 , 32 , Tau-oriented strategies Given its critical role in pathogenesis of AD, drug development may also target the production, processing phosphorylation and aggregation of Tau protein Conclusions and future directions To date, treatment of AD relies on the symptomatic effects of cholinesterase inhibitors and NMDA-receptor antagonists.

References 1. Alzheimer's disease. Geneva: WHO; Active ageing: a policy framework. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol.

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Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity. Bioorg Med Chem Lett. Sweden: J Neurosci.

Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies
Alzheimers Disease: Targets for New Clinical Diagnostic and Therapeutic Strategies

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