Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative condition that results in severe cognitive and functional decline in sufferers and for which there are currently no effective treatments to halt or reverse disease progression. AD is the most common form of dementia and age is the major risk factor for this disease. With worldwide population structures changing as increasing number of individuals survive into old age, there is urgent need for novel disease modifying treatments for this condition, which has profound effects upon sufferers in addition to those around them. Some of us have previously developed a peptide inhibitor of Aβ1-42 aggregation (RI-OR2-TAT) that has been shown to reduce Aβ1-42 pathology in vivo in mouse models of AD. ∼1690 copies of RI-OR2-TAT have been covalently attached to nanoliposome carrier particles forming Peptide Inhibitor NanoParticles (PINPs), and this study investigated the effect of PINPs upon Aβ1-42 aggregation at the molecular level. Our results show that PINPs are able to reduce Aβ1-42 aggregation and do so by binding early (oligomers) and late (fibrillar) stage aggregates. These results highlight the ability of PINPs to disrupt the formation of multiple Aβ1-42 aggregates capable of causing neurotoxicity and thus provide a strong case for PINPs to be carried forward into early stage clinical trials as a novel therapeutic option for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the leading cause of dementia [1]
This study investigated the interactions between Peptide Inhibitor NanoParticles (PINPs) and Aβ1-42 at the molecular level in an attempt to evaluate the potential for PINPs to be carried forward as a novel treatment for AD
Our results indicate that PINPs are able to suppress fibril formation and elongation as co-incubation of Aβ1-42 with PINPs resulted in much fewer dense Aβ1-42 aggregations than was observed with Aβ1-42 alone
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the leading cause of dementia [1]. The senile plaques are formed by self-aggregation of the amyloid-β (Aβ) peptide, which is cleaved from a precursor protein – APP – by β- and γ- secretases, whilst the neurofibrillary tangles are formed from hyperphosphorylated Tau protein. Current therapies available to sufferers of AD are aimed at alleviating the symptoms of the disease rather than impacting upon disease progression. These treatments have been shown to reduce the rate of cognitive decline in AD sufferers, their lack of effect upon the underlying cause of the disease means that their beneficial effect is only temporary. No DMTs have progressed past phase III trials and, there are none available for the treatment of AD
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