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Wednesday, May 31, 2017

Is it feasible to cure prodromal Alzheimer's disease with a peptide nasal spray?


Abstract (as presented by the authors of the scientific work):

"Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aβ(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aβ(25-35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Cure prodromal Alzheimer's disease with a peptide nasal spray self-made word-cloud




Discussion (as presented by the authors of the scientific work):

"In this study, we demonstrated that the peptide R8‐Aβ(25–35) reduced the formation of amyloid fibrils by Aβ40 in vitro, as well as amyloid plaques and disease manifestation in vivo. In a companion study, therapeutic peptides designed by the same modular principle also delayed disease in the R6/2 transgenic mice, a widely used mouse model for Huntington's disease (unpublished data). Thus, our data illustrated the possibility that this principle may be extended to design therapeutic peptides for other neurodegenerative diseases.

A variety of therapeutic peptides to decrease the formation of amyloid fibrils has been proposed (Funke & Willbold, 2012); our bipartite design works by attaching a polyR stretch to the peptide sequence derived from the disease‐specific pathogenic peptide/protein prone to aggregation. This approach possessed several unique features and advantages. First, the sequence directly taken from the pathogenic peptide/protein not only significantly reduced the labors of finding and optimizing a suitable peptide sequence, but also guaranteed high affinity with the target through its self‐aggregating property. Second, the multi‐charges in polyR rendered the designed therapeutic peptide (i) soluble in an aqueous environment and therefore simplifying the processes of synthesis and subsequent application, (ii) cell‐penetrable (Mitchell et al, 2000), making it suitable for both extracellular and intracellular peptide/protein aggregation, and (iii) able to slow down oligomer/amyloid formation by charge repulsion after its binding to the pathogenic peptide/protein. Third, combination of the polyR with the sequence from disease‐specific pathogenic protein/peptide provided great feasibility and flexibility in applying this design across different misfolded aggregate‐associated diseases.

Although many therapeutic peptides have been designed, only a few of them were tested in vivo (Permanne et al, 2002; van Groen et al, 2008; Frydman‐Marom et al, 2009; Funke et al, 2010; Shukla et al, 2013; Lin et al, 2016). In this study, we have demonstrated the feasibility of intranasal administration of therapeutic peptidic prodrugs. When combined with technology in delivery, our study showed a proof of therapeutic principle for neurodegenerative diseases through intranasal delivery. The dose used in this study was only 2 nmoles (6 μg) per day, which was quite low compared with previous studies (Permanne et al, 2002; van Groen et al, 2008; Frydman‐Marom et al, 2009; Funke et al, 2010). Using this dosage, we attempted to investigate the level of the therapeutic peptide in the brain during consecutive intranasal treatment (experimental set 5 in Appendix Figs S3 and S6). However, the peptide concentration was low and could not be reliably detected. As shown in Fig 5, after three consecutive treatments at higher amount (9 nmoles), there was 5.16 nmole of the peptide in the brain at 6 h after the final treatment and 3.62 nmole of the peptide in the brain 24 h after the final treatment. Although the current method was geared toward maximizing our ability to detect the intracerebral peptide rather than producing an accurate number in its efficiency in brain entrance, an estimated value was still achievable. Since the treatment continued for 3 days, the amount of intracerebral peptide before the 3rd dose was expected not to be more than 3.62 nmole observed 24 h after the 3rd treatment. Thus, at least 1.54 nmole (5.16 minus 3.62) or 17% of the daily dose of 9 nmole peptide entered brain. These results indicate that this peptide had a reasonably high therapeutic efficacy. Future studies will be conducted for optimal dosage.

The peptide treatment did not significantly decrease the numbers of the ThS‐positive amyloid plaques, but reduced the size of the individual plaques and the total area of these plaques. One possibility is that most of the Aβ reduction is diffusely deposited Aβ. Alternatively, when we started treatment, the cores of plaques might have already formed at 4 months, but our peptide slowed down the speed of the accumulation of the transgenic Aβ of these plaques. Moreover, when we quantified SDS‐soluble Aβ and SDS‐insoluble Aβ separately (Fig 4C–F), we found that SDS‐insoluble Aβ reduced after peptide treatment whereas SDS‐soluble Aβ increased. Aβ accumulation is due to the imbalance of Aβ production and Aβ degradation. Our peptide treatment likely functions to inhibit Aβ from self‐association, but may not directly impact on the Aβ degradation rate. The clearance of excessive Aβ depends on several Aβ‐degrading enzymes, such as neprilysin (the most important one) and insulin‐degrading enzyme, which were found to be downregulated in old mice (Caccamo et al, 2005). However, by preventing Aβ from aggregation, our peptide could render it more accessible to these Aβ‐degrading enzymes and/or other degradation machinery in the brain. Recently, it has been reported that polyhydroxycurcuminoids upregulate neprilysin in the brain (Chen et al, 2016). Combining the peptide inhibitor and the neprilysin activator might additively enhance Aβ clearance.

Comparing peptide therapy and antibody therapy, the cost of peptide synthesis is much lower than the cost of producing monoclonal antibody. Moreover, as the peptide worked in vivo without incorporating non‐natural or D‐form amino acid, there was no worry for the toxicity caused by non‐natural amino acids. Consistent with this, the preliminary tests for liver and kidney function indicated no clear toxicity in the mice receiving the peptide for 8 months (Appendix Fig S7).

Lastly, to determine whether the peptide treatment induced an antibody response against Aβ peptide, the serum of the mice treated for 15 days was tested and showed no evidence of immunoreactivity against the peptide (experimental set 6 in Appendix Figs S3 and S8). In summary, intranasal administration of our bipartite peptide designed on the principle of modular combination may serve as an effective and user‐friendly disease‐modifying therapy for Alzheimer's disease and a template for developing effective therapy against other protein aggregation‐associated diseases."


Full-text access of the referenced scientific work:

Cheng YS, Chen ZT, Liao TY, Lin C, Shen HC, Wang YH, Chang CW, Liu RS, Chen
RP, Tu PH. An intranasally delivered peptide drug ameliorates cognitive decline
in Alzheimer transgenic mice. EMBO Mol Med. 2017 May;9(5):703-715. doi:
10.15252/emmm.201606666. PubMed PMID: 28356312; PubMed Central PMCID: PMC5412883.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412883/


Further reading:

Alzheimer's disease (MedlinePlus):
"Alzheimer's disease (AD) is the most common form of dementia among older people. Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities.
AD begins slowly. It first involves the parts of the brain that control thought, memory and language. People with AD may have trouble remembering things that happened recently or names of people they know. A related problem, mild cognitive impairment (MCI), causes more memory problems than normal for people of the same age. Many, but not all, people with MCI will develop AD.
In AD, over time, symptoms get worse. People may not recognize family members. They may have trouble speaking, reading or writing. They may forget how to brush their teeth or comb their hair. Later on, they may become anxious or aggressive, or wander away from home. Eventually, they need total care. This can cause great stress for family members who must care for them.
AD usually begins after age 60. The risk goes up as you get older. Your risk is also higher if a family member has had the disease.
No treatment can stop the disease. However, some drugs may help keep symptoms from getting worse for a limited time.
...read more".

Amyloid beta (Wikipedia):
"Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are crucially involved in Alzheimer's disease as the main component of the amyloid plaques found in the brains of Alzheimer patients.[2] The peptides result from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The seeds or the resulting amyloid plaques are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.[3][4]
A recent study suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.[5]
...read more".

Prodromal Alzheimer's (Glasgow Memory Clinic):
"Q: What is Prodromal Alzheimer’s disease?
A: Prodromal Alzheimer’s disease is the very early form of Alzheimer’s when memory is deteriorating but a person remains functionally independent.
Q: How is Prodromal Alzheimer’s disease diagnosed?
A: A person must have memory impairment (mild cognitive impairment) but also have a positive biomarker test.  The biomarker tests can be a protein that is measured in spinal fluid or a new type of scan (PET scan) that can detect the amyloid protein that accumulates in the brain in people with Alzheimer’s disease.
Q: Why is there so much interest in Prodromal Alzheimer’s disease?
A: The purpose of identifying people with this very early stage of Alzheimer’s disease allows the opportunity for early intervention, for example to discover if a vaccine can prevent the condition deteriorating.
...read more".


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