The Alzheimer disease market

Qian, Xiaoxiao; Hamad, Bashar; Dias-Lalcaca, Gus

doi:10.1038/nrd4749

Cited by 50 publications

(34 citation statements)

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“…Cognition enhancing drugs [Buccafusco, 2009;Husain and Mehta, 2011;Chen et al, 2014], bsecretase cleaving enzyme inhibitors [Sheridan, 2015], ApoE-directed therapeutics [Fonseca et al, 2009;Cramer et al, 2012;LaFerla, 2012;Strittmatter, 2012], HDACi [Peleg et al, 2010;Wiley et al, 2011;Govindarajan et al, 2012;Gr€ aff et al, 2012;Nebbioso et al, 2012;Ricobaraza et al, 2012;Sung et al, 2013;Coppedè, 2012;Falkenberg and Johnstone, 2014;Narayan et al, 2015], glycogen synthase kinase-3 inhibitors [Maqbool et al, 2016], polysulfides [Xu et al, 2014], retinoids [Fukasawa et al, 2012;Shearer et al, 2012], suppressing RAGE (receptor for advanced glycation end products) [Deane et al, 2012;Sorci et al, 2013], phosphodiesterase inhibitors [Feil et al, 2014;Gurney et al, 2015], and amyloid-targeting immunotherapies [Busche et al, 2015;Qian et al, 2015] are some of the more active areas of current AD drug development research.…”

Section: Alzheimer Diseasementioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Alzheimer Diseasementioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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“…27 Today, enormous effort is devoted to the design of small molecule BACE1 inhibitors, some of which are currently in Phase II/III clinical trials. 28 Alternative strategies aim to inhibit BACE1 allosterically by BACE1-binding antibodies or peptides, to target Ab by antibodies, or to develop vaccines against Ab. 28,29 Early alterations of network activity in AD Long unrecognized in the clinical care of AD patients, in particular at early stages of the disease, epileptiform activity is now receiving increasing attention, as it appears to play an important role in AD pathogenesis and progression.…”

Section: Role Of Bace1 In Admentioning

confidence: 99%

“…28 Alternative strategies aim to inhibit BACE1 allosterically by BACE1-binding antibodies or peptides, to target Ab by antibodies, or to develop vaccines against Ab. 28,29 Early alterations of network activity in AD Long unrecognized in the clinical care of AD patients, in particular at early stages of the disease, epileptiform activity is now receiving increasing attention, as it appears to play an important role in AD pathogenesis and progression. 30,31 AD is associated with an enhanced risk of seizures, and patients displaying (subclinical) epileptiform activity or overt seizures show earlier onset of cognitive decline and faster transition into severe dementia.…”

Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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“…[25][26][27][28] Thesoluble Ab42 monomers first undergo conformational transitions into partially unfolded intermediates,a nd subsequently selfassemble into toxic oligomers that further aggregate into insoluble fibrils (see 1 in Scheme 1a). [25][26][27][28] Thesoluble Ab42 monomers first undergo conformational transitions into partially unfolded intermediates,a nd subsequently selfassemble into toxic oligomers that further aggregate into insoluble fibrils (see 1 in Scheme 1a).…”

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confidence: 99%

Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

Sun

Liu

et al. 2019

Angew Chem Int Ed

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Protein misfolding and aberrant aggregations are associated with multiple prevalent and intractable diseases. Inhibition of amyloid assembly is apromising strategy for the treatment of amyloidosis.R eported here is the design and synthesis of areactive conjugated polymer,apoly(p-phenylene vinylene) derivative,f unctionalizedw ith p-nitrophenyl esters (PPV-NP) and it inhibits the assembly of amyloid proteins, degrades preformed fibrils,a nd reduces the cytotoxicity of amyloid aggregations in living cells.PPV-NP is attached to the proteins through hydrophobic interactions and irreversible covalent linkage.P PV-NP also exhibited the capacity to eliminate Ab plaques in brain slices in ex vivo assays.T his work represents an innovative attempt to inhibit protein pathogenic aggregates,and may offer insights into the development of therapeutic strategies for amyloidosis.Proteins are one of the most important basic bio-macromolecules in organisms.T he aberrant assembly of proteins into insoluble amyloid aggregates would disrupt their biological functions and result in the generation of toxic intermediates and amyloidosis,w hich are relevant to ar ange of intractable human disorders such as Alzheimersd isease, Parkinsonsd isease,d ialysis-related amyloidosis,a nd type-2 diabetes. [1][2][3][4][5][6][7] On this account, numerous approaches to inhibit amyloid assembly have emerged, ranging from synthetic and natural small-molecule compounds, [4,8,9] peptides, [10,11] antibodies, [12] and nanoparticles [13,14] to artificial chaperones, [15] which make certain achievements to the inhibition of pathogenic aggregates.H owever,t od ate,t he pharmacological treatments for these diseases are still unsatisfactory. [16] Rational chemical designs to effectively inhibit and disrupt the amyloid assembly are still of great significance.In fact, most previous inhibitors functioned through noncovalent interactions,s uch as hydrophobic interactions, p-p stacking,e lectrostatic interactions,a nd hydrogen bonding. These interactions are intrinsically weak and susceptible to the surrounding environment. [17] Thef luctuation of either pH or temperature may induce the disassembly of inhibitor/ protein complexes,and would make the inhibitors invalid. In contrast, covalent interactions are more chemically stable and not susceptible to the fluctuation of surrounding environment. Reactions between inhibitors and proteins are usually irreversible,and inhibitors could remain attached to proteins for long time.T hus,d eveloping new inhibiting materials for amyloid assembly with acovalent-linking strategy is expected to lead to prolonged duration of inhibition and improved efficiency.T he amphiphilic conjugated polymers are considered pioneering materials in the biomedical field owing to their unique photoelectrical properties. [18][19][20][21][22][23][24] Here,w e designed and synthesized ar eactive conjugated polymer, ap oly(p-phenylene vinylene) derivative,f unctionalized with p-nitrophenyl active esters (PPV-NP) to inhibit protein assembly and disru...

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The Alzheimer disease market

Cited by 50 publications

References 1 publication

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

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