A study investigating the blood-brain barrier penetration, distribution
      and elimination of retro-inverso peptides as candidate treatments for
      Alzheimer’s disease
Creators: name: Michael, Maria
Publisher: name: Lancaster University
Year: 2017

description: Alzheimer’s disease (AD) is an age-related neurodegenerative disease that
      mainly affects elderly individuals. The disease is characterised
      clinically by cognitive decline and neuropsychiatric symptoms, while its
      pathological features are the accumulation of senile plaques and
      neurofibrillary tangles in the brain. Aβ pathology is a central component
      of the disease. Early aggregated forms of Aβ known as “soluble oligomers”
      are believed to be a potent neurotoxic agent responsible for nerve cell
      damage and loss of synapses, so contributing to memory and learning
      deficits. Therefore, inhibiting the formation of these early aggregates
      could provide a novel approach to the treatment of AD.
      
      
      A retro-inverso peptide, RI-OR2-TAT, has been developed previously in
      Lancaster, and this demonstrated good inhibition of early-stage Aβ
      aggregation, but only at high concentrations of inhibitor relative to Aβ.
      An improved peptide system was subsequently developed involving attachment
      of RI-OR2-TAT onto the surface of a lipid nanoparticle scaffold
      (nanoliposome). The resulting “Peptide inhibitor nanoparticles” (PINPs)
      demonstrated much more potent inhibition of aggregation, and could
      penetrate through an artificial BBB. In this project, RI-OR2-TAT, PINPs
      and a novel retro-inverso peptide, RI-OR2-NAG, were examined for their
      ability to cross the intact and functional blood-brain barrier (BBB) of WT
      mice. Their accumulation in the brain, distribution in peripheral tissues,
      and possible modes of excretion, were examined in WT mice, 1 h following
      peripheral administration. 
      
      
      In fluorescent imaging studies, fluorescein-labelled versions of
      RI-OR2-TAT, RI-OR2-NAG and PINPs all demonstrated effective penetration
      across an integral BBB and accumulation in the cortex, hippocampus, and
      dentate gyrus of the brain, where they were mainly co-localised with glial
      cells. Luminex technology was used to study the distribution of the first
      two peptides in the brain, heart, lungs, stomach, liver, spleen, kidneys
      and small intestine. The results of this study confirmed that these
      peptides accumulate in small amounts in the brain, but they are mainly
      found in the small intestine, suggesting a possible elimination route
      through bile secretions into the duodenum, followed by excretion through
      the faeces or reabsorption back into the general circulation, for possible
      excretion through the urine. Finally, as part of the project, the
      anti-aggregatory properties of the RI-OR2-NAG peptide were investigated,
      and this proved to be a more effective inhibitor of Aβ aggregation than
      RI-OR2-TAT.
      
      
      In conclusion, the use of liposomes as an effective carrier nanosystem for
      targeted delivery could be extended to the RI-OR2-NAG peptide. The results
      of this PhD thesis project are encouraging and it is hoped that a version
      of these peptides can progress into clinical trials.