An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer’s disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet.
Alzheimer’s disease (AD) is a progressive, irreversible brain disorder with an unclear etiology and no cure. Symptoms include memory loss, confusion, impaired judgment, disorientation, and loss of language skills . In the past two decades, a large number of experimental studies have established a pathological role for Aβ in AD –. However, recent debate has focused on whether Aβ amyloid fibrils or Aβ soluble oligomers are the main neurotoxic species which contribute to neurodegeneration and dementia. Considerable evidence has indicated that amyloid fibrils are toxic . Yet, recent studies support the notion that it is actually the early soluble oligomers that are the primary neurotoxic agents –. In particular, 56 kDa (56*) dodecameric oligomers of Aβ were shown to correlated with the deterioration of cognitive functions in AD model mice and their reintroduction into normal brains resulted in memory impairment , .
Despite a significant increase in our understanding of the pathogenesis of AD, therapeutic options are still very limited and aim only at amelioration of symptoms. More recent therapeutic approaches aim at removing aggregated Aβ and decreasing the production of the pathogenic Aβ42 peptide . Yet, novel observations suggest that the endogenous Aβ peptides may normally have a crucial role in activity-dependent regulation of synaptic vesicle release , hence methods used to abolish all Aβ production may in fact aggravate synapse loss in Alzheimer’s disease. Therefore, it may be advantageous to target the earliest stages of Aβ oligomerization, thus removing all potential toxic species of Aβ. Indeed, pervious work by our group and others has already demonstrated that targeting the early process of Aβ molecular recognition is a very promising approach for the treatment of AD –.
Plants have a long history as a rich source of new bioactive compounds for drug discovery and may have advantages in relation to efficacy. Several reports documented the effectiveness of herbal extracts over isolated material, in protection against lipid peroxidation  and anti cancer effects . For example, a mixture of carotenoids have been found to be more effective than any one single carotenoid in protecting liposomes against lipid peroxidation .
Recent studies have shown inhibition of Aβ plaque formation in vitro and in vivo by compounds from natural sources –. Still, evidence for the capability of common edible elements to inhibit Aβ oligomerization in vivo remains a challenge. Cinnamon is widely used by humans, both as a spice and as a traditional medicine. It is, perhaps, one of the oldest herbal medicines, having been mentioned in the Bible (Exodus, Proverbs and Song of Songs) and in Chinese texts as long as 4,000 years ago . The unique healing abilities of cinnamon are due to various components such as cinnamaldehyde, eugenol, cinnamyl acetate, and cinnamyl alcohol, in addition to a wide range of other volatile substances including safrole, coumarin and cinnamic acid esters . Cinnamon has unique medicinal abilities such as blood sugar control , anti-oxidant , anti inflammatory  and anti-microbial activities . Furthermore, it was demonstrated that cinnamon has an inhibitory effect on Tau aggregation related to AD , as well as pharmacological properties in the treatment of type II diabetes . Studies have shown that the potentially toxic compounds in cinnamon bark are found primarily in lipid soluble fractions but are present only in extremely low levels in water soluble cinnamon extracts  which are therefore considered highly safe for uptake. Here, we demonstrate the use of a natural substance based on aqueous cinnamon extract (CEppt) as an efficacious therapeutic agent that inhibits Aβ oligomer formation and ameliorates AD symptoms. In addition, we suggest the use of an efficacious platform for screening molecules as AD drugs using in vitro cell culture and in vivo AD fly and aggressive AD mouse model.