The Quest for Small Molecules as Amyloid Inhibiting Therapies for Alzheimer's Disease

Amijee, Hozefa; Scopes, D. I. C.

doi:10.3233/jad-2009-1044

Cited by 60 publications

(56 citation statements)

References 102 publications

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“…AD subjects depict significant elevation in serum luteinizing hormone (LH) concentrations [130]. Treatments targeting LH can modulate cognitive behaviour in aged APP transgenic mice, and NSAIDS Ibuprofen, indomethacin [126] Thiazolidinedione derivatives Rosiglitazone, pioglitazone [124] HRT Leuprolide acetate [131] Natural compounds/extracts Green tea, Ginkgo biloba extract, curcumin, inositol [132,170] Ab aggregation Small molecule compounds Nitrophenols, curcumin [132,133,138] Metal chelators Clioquinol, PBT2 [139,140] Monoclonal antibody therapy Bapineuzumab, solanezumab, GSK-933776, MABT-5102A [152,153] Peptidic and non-peptidic compounds RS-0406, SEN1269 [141] Ab clearance Metal chelators PBT2 [140] Antibody treatment Bapineuzumab, solanezumab, GSK-933776, MABT-5102A, anti-Ab (2H6-D) [11,142,152,153] Immunotherapy AN-1792, CAD-106, Lu AF20513, ACC-001, V-950, ACI-24, UB-311 [148,149] …”

Section: Targeting Amyloid B In the Retinamentioning

confidence: 99%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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Section: Targeting Amyloid B In the Retinamentioning

confidence: 99%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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“…[23][24][25], and references therein). A general conclusion of these studies is that many small molecules redirect the aggregation cascade rather than inhibiting it completely (26).…”

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confidence: 99%

Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways

Ladiwala

Dordick

Tessier

2011

Journal of Biological Chemistry

175

173

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In protein conformational disorders ranging from Alzheimer to Parkinson disease, proteins of unrelated sequence misfold into a similar array of aggregated conformers ranging from small oligomers to large amyloid fibrils. Substantial evidence suggests that small, prefibrillar oligomers are the most toxic species, yet to what extent they can be selectively targeted and remodeled into non-toxic conformers using small molecules is poorly understood. We have evaluated the conformational specificity and remodeling pathways of a diverse panel of aromatic small molecules against mature soluble oligomers of the A␤42 peptide associated with Alzheimer disease. We find that small molecule antagonists can be grouped into three classes, which we herein define as Class I, II, and III molecules, based on the distinct pathways they utilize to remodel soluble oligomers into multiple conformers with reduced toxicity. Class I molecules remodel soluble oligomers into large, off-pathway aggregates that are non-toxic. Moreover, Class IA molecules also remodel amyloid fibrils into the same off-pathway structures, whereas Class IB molecules fail to remodel fibrils but accelerate aggregation of freshly disaggregated A␤. In contrast, a Class II molecule converts soluble A␤ oligomers into fibrils, but is inactive against disaggregated and fibrillar A␤. Class III molecules disassemble soluble oligomers (as well as fibrils) into low molecular weight species that are non-toxic. Strikingly, A␤ non-toxic oligomers (which are morphologically indistinguishable from toxic soluble oligomers) are significantly more resistant to being remodeled than A␤ soluble oligomers or amyloid fibrils. Our findings reveal that relatively subtle differences in small molecule structure encipher surprisingly large differences in the pathways they employ to remodel A␤ soluble oligomers and related aggregated conformers.A central tenet of protein folding is that a given amino acid sequence encodes a single folded structure (1). By analogy, one would expect that a given protein sequence would encode a single misfolded structure (e.g. a single amyloid fibril conformation). Instead, each protein sequence encodes numerous aggregated isoforms that possess unique secondary and tertiary structures (2-12). Previous work has firmly established that small, prefibrillar conformers (herein referred to as soluble oligomers) of diverse polypeptides are the most toxic aggregates both in vitro and in vivo (11,(13)(14)(15)(16)(17). However, elucidating the structural attributes of such toxic conformers that differentiate them from their non-toxic counterparts has proven difficult (see Refs. 11 and 18 -22 for recent progress).Significant evidence linking protein misfolding to cellular toxicity in numerous aggregation disorders has motivated the search for small molecules that prevent aggregation (see Refs. 23-25, and references therein). A general conclusion of these studies is that many small molecules redirect the aggregation cascade rather than inhibiting it completely (26). In hind...

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“…Due to the proposed central role of amyloid in AD development, it has enjoyed great attention from the pharmaceutical industry as well as the academic society (Amijee and Scopes, 2009). Currently, FDA and EMEA approved drugs for AD are all symptomatic, including four acetylcholinesterase inhibitors and one NMDA-antagonist.…”

Section: An Attractive Therapeutic Targetmentioning

confidence: 99%

Amyloid and Alzheimer’s disease

Lei

2010

Protein Cell

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A CLASSICAL HISTOPATHOLOGICAL HALLMARKAlzheimer's disease (AD) is the most prevalent neurodegenerative disease afflicting over 30 million patients worldwide. The typical symptoms of AD include memory loss and impairment of cognitive function, and currently, there is no available approach to cure the disease. The projected fast increase of the senior population is a growing burden for the international society in terms of both medical cost and patient care. Since the first case examination in1907, amyloid has been associated with the disease named after its pioneer Dr. Alois Alzheimer. A classical histopathological hallmark for AD is the extracellular deposition of amyloid plaques found in the postmortem brain of AD patients, along with the intracellular neurofibrillary tangles (NFT). It is widely believed that amyloid is the cause of all the symptoms and the eventual death of AD patients. This so called "amyloid hypothesis" is dominant in the field of AD research, and a good portion of the work in this field has been devoted to the mechanism and pathological effect of amyloid formation.

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The Quest for Small Molecules as Amyloid Inhibiting Therapies for Alzheimer's Disease

Cited by 60 publications

References 102 publications

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways

Amyloid and Alzheimer’s disease

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