Modulation of amyloid‐β aggregation and toxicity by inosose stereoisomers

Abstract

Inositol is a simple polyol with eight naturally occurring stereoisomers, the most common of which are myo-inositol, chiro-inositol, epi-inositol, and scyllo-inositol [1]. myo-Inositol is the most abundant isomer and is a ubiquitous component of all eukaryotic cells. We have shown that scyllo-inositol may represent a potential therapeutic agent for amyloid disorders such as Alzheimer's disease (AD) [2,3]. We showed that myoinositol complexes with amyloid-b (Ab)42 in vitro to form a small, stable micelle [4]. The ability of inositol stereoisomers to interact with and stabilize small Ab complexes was subsequently addressed [5]. CD spectroscopy demonstrated that epi-inositol and scylloinositol, but not chiro-inositol, were able to induce a structural transition from a random to a b-structure in Ab42. Furthermore, electron microscopy demonstrated that scyllo-inositol stabilizes small aggregates of Ab42 that are nontoxic to nerve growth factor (NGF)-differentiated PC-12 cells and primary human neuronal cultures.We then examined the in vivo effects of the inositol stereoisomers. myo-Inositol, epi-inositol and scyllo-inositol were administered to the TgCRND8 mouse model of AD, which demonstrates age-associated cognitive deficits and AD-like pathology [2,6]. myo-Inositol was effective in vitro but was ineffective in vivo [2,5]. epiInositol had some initial positive results as a prophylactic treatment, but these positive effects were not sustained with disease advancement [2]. scyllo-Inositol treatment, however, resulted in a significant improvement in cognitive function, synaptic function, and lifespan. Significant decreases in Ab40 and Ab42 levels, vascular amyloid levels, plaque size and area were also observed [2]. Therefore, scyllo-inositol is effective at Amyloid-b (Ab) aggregation and amyloid formation are key pathological features of Alzheimer's disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer's disease. We have previously identified inositol stereoisomers as exhibiting stereospecific inhibition of Ab aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on Ab fibrillogenesis as determined using CD and fluorescence spectroscopy and negativestain electron microscopy. The inososes differ from inositols by the oxidation of one of the hydroxyl groups to a ketone. These molecules help in the further elucidation of the structure-activity relationships of inositolAb interactions and identify both allo-inositol and epi-2-inosose as in vitro inhibitors of Ab aggregation.Abbreviations AD, Alzheimer's disease; Ab, amyloid-b; HMIT, hydrogen myo-inositol transporter; NGF, nerve growth factor; SMIT, sodium myo-inositol transporter; TFE, trifluoroethanol.

Blood-Borne Amyloid-β Dimer Correlates with Clinical Markers of Alzheimer's Disease

“…A number of potential AD therapeutic strategies targeting A␤ and its oligomers (so called disease-modifying drugs) are currently being investigated, including immunotherapy designed to promote A␤ clearance (Nicoll et al, 2006), secretase inhibitors, which prevent A␤ generation (Olson and Albright, 2008), scyllo-inositol, which is reported to inhibit toxic A␤ oligomers binding to membranes (Nitz et al, 2008), and PBT2-a second generation MPAC that inhibits the formation of toxic A␤ oligomers (Adlard et al, 2008). The assessment of outcomes of the clinical trials is often difficult to define as they rely on highly variable neuropsychometric tests.…”

Cyclitols in maturing grains of wheat, triticale and barley

“…myo-inositol, can change accumulation of other soluble carbohydrates, particularly RFOs and modify tolerance of grains and seedlings to abiotic stresses. On the other hand, D-pinitol and D-chiro-inositol indicate some health benefits both cyclitols and their galactosides can be helpful compounds in treatment of type 2 diabetes (lowering glucose level in blood), polycystic ovary syndrome (Yoshida et al 2006), and Alzheimers disease (Nitz et al 2008). Pinitol also possesses anti-inflammatory (Sethi et al 2008) and anti-viral properties (Zhan et al 2006) and has been implicated in the prevention of cardiovascular diseases (Choi et al 2009).…”

Structure−Activity Relationships in Peptide Modulators of β-Amyloid Protein Aggregation: Variation in α,α-Disubstitution Results in Altered Aggregate Size and Morphology

“…These include inhibition or modulation of proteases involved in the cleavage of Aβ from the amyloid precursor protein (APP) (25)(26)(27), the use of antibody therapy (through passive immunizations with anti-Aβ antibodies (28)(29)(30) and nonantibodybased natural mechanisms) (31)(32)(33), small organic molecules or nonpeptides such as inositols, phenols, and indoles (26,(34)(35)(36)(37)(38) and peptides (34). Interest in peptidebased aggregation mitigators of Aβ aggregation has intensified, because peptides are generally more potent and display higher specificity of action and fewer toxicological challenges than small organic molecules.…”