Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

McLaurin, J.; Kierstead, Meredith E.; Brown, Mary Elizabeth; Hawkes, Cheryl A.; Lambermon, Mark H. L.; Phinney, Amie L.; Darabie, Audrey A.; Cousins, Julian E.; French, John B.; Lan, Melissa F.; Chen, Fusheng; Wong, Suzanne; Mount, Howard T.J.; Fraser, Paul E.; Westaway, David; George-Hyslop, Peter St

doi:10.1038/nm1423

Cited by 334 publications

(320 citation statements)

References 34 publications

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“…Spine loss was also fully prevented by co-application to the slices of an N-terminal monoclonal antibody to Aβ (6E10) together with the soluble oligomers; denatured (boiled) 6E10 had no rescue effect. We also examined scyllo-inositol (AZD-103), a myo-inositol steroisomer shown by Joanne McLaurin and colleagues to decrease Aβ plaque number and size and prevent behavioral deficits in an APP transgenic mouse line [39]. At 5 uM concentrations, scyllo-inositol co-administered with the soluble oligomers fully prevented the spine loss, whereas a known inactive stereoisomer, chiroinositol, did nothing.…”

Section: Cell-derived Oligomers Decrease Dendritic Spine Density In Hmentioning

confidence: 99%

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Selkoe

2008

Behavioural Brain Research

912

471

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SummaryDuring the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid β-protein (Aβ) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Aβ42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Aβ during some kinds of synaptic activity. Elevated levels of soluble Aβ42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers --at picomolar concentrations --can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Aβ trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Aβ antibodies or small-molecule modulators of Aβ aggregation. This therapeutic progress has been accompanied by advances in imaging the Aβ deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

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Section: Cell-derived Oligomers Decrease Dendritic Spine Density In Hmentioning

confidence: 99%

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Selkoe

2008

Behavioural Brain Research

912

471

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“…Since myo-inositol is a native constituent of the CNS, the effects of the various inositol stereoisomers on Abaggregation and toxicity were examined Nitz et al, 2008] and showed a stereospecific interaction of inositol with Ab that required all hydroxyl groups to be in an equatorial position for maximal activity, the scyllo-inositol isomer . scyllo-Inositol administration to TgCRND8 mice prevented Ab-induced cognitive deficits, plaque formation, synaptotoxicity, and early death [McLaurin et al, 2006]. These effects were seen in both prophylactic and treatment studies.…”

Section: Lipid-based Small Molecule Inhibitorsmentioning

confidence: 75%

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

Hawkes

McLaurin

2009

Drug Development Research

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Alzheimer disease (AD) is characterized pathologically by extracellular amyloid deposits composed of Ab peptide, neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau, and a deficit of cholinergic neurons in the basal forebrain. Presently, only symptomatic therapies are available for the treatment of AD and these therapies have a limited time frame of utility. Amyloid disorders represent the effects of chronic Ab production and are not a secondary pathological effect caused by a distant trigger; therefore targeting Ab is a viable pursuit. In this review, we will discuss the various small molecule antiaggregation inhibitors that have been reported in the literature, with emphasis on compounds that are presently being investigated in clinical trials. Drug Dev Res 70 : 111-124, 2009.

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“…[63] In the same mouse model scyllo-inositol, when administered orally, inhibited the aggregation of Aβ and reduced the severity of several of the symptoms of Alzheimer's disease including impaired cognition, altered synaptic physiology, cerebral Aβ pathology and accelerated mortality. [64] These effects were observed whether the scyllo-inositol was administered before symptoms first appeared or several months after their first appearance. The administration of scyllo-inositol also rescues hippocampal function and restores memory function in animals with pre-existing Aβ oligomers.…”

Section: Scyllo-inositol and Neurological Disordersmentioning

confidence: 99%

“…[48] epi-Inositol has an initial impact on the aggregation of amyloid-β associated with Alzheimer's disease but is unable to maintain that impact over time. [64] The non-mammalian biology of epi-inositol is discussed in the Supporting Information (SI_2).…”

Section: Biology and Medicinementioning

confidence: 99%

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

2015

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Cell signalling via inositol phosphates, eg the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-and scyllo-) and derivatives rarer or thought not to exist in nature. However, recently, neoand D-chiro-inositol hexakisphosphates were revealed in both terrestrial and aquatic ecosystems, highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, e.g. scyllo-inositol (neurodegenerative diseases), and D-chiro-inositol (diabetes). It is timely to consider exploration of roles and applications of "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo-series.

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Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

Cited by 334 publications

References 34 publications

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

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