A survey of peptides with effective therapeutic potential in Alzheimer's disease rodent models or in human clinical studies

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia. Today, only palliative therapies are available. The pathological hallmarks of AD are the presence of neurofibrillary tangles and amyloid plaques, mainly composed of the amyloid-β peptide (Aβ), in the brains of the patients. Several lines of evidence suggest that the increased production and/or decreased cleavage of Aβ and subsequent accumulation of Aβ oligomers and aggregates play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. A wide range of Aβ binding peptides were investigated to date for therapeutic purposes. Only very few were shown to be effective in rodent AD models or in clinical studies. Here, we review those peptides and discuss their possible mechanisms of action.

Fig. (1)

APP processing. The transmembrane protein APP can be processed along two main pathways, non-amyloidogenic pathway and amyloidogenic pathway. In the non-amyloidogenic pathway, α-secretase cleaves in the middle of the Aβ region and releases a soluble APP fragment (sAPPα) and a C83 carboxy-terminal fragment. In the amyloidogenic pathway, APP is sequentially cleaved by β-secretase and γ- secretase. Aβ is released and aggregates further to oligomers, fibrils and neurotoxic amyloid plaques. ApoE can act as a chaperone of Aβ, promoting its conformational transformation from soluble Aβ into toxic aggregates. Aβ plaques induce inflammatory responses and oxidative stress, and thereby cause neuronal loss. Strategies for therapeutic intervention in AD include α-secretase activation, β-/γ-secretase inhibition, Aβcleavage, anti-inflammation, anti-oxidative stress, etc. Several therapeutic peptides act as β-sheet breakers, anti-inflammation and anti-oxidative stress agents.Therapeutic peptides which have been studied both in vitro and in vivo are illustrated in the figure.

Fig. (2)

Illustration of KLVFFAE (Aβ(16-22)), SRE of Aβ. Aβ1-40 and Aβ1-42 are the major forms of Aβ peptides in the brain. Here, the sequences of both peptides are illustrated. The SRE part of Aβ, KLVFFAE, is indicated.

Fig. (3)

Chemical structure of PPI-1019. The sequence of PPI- 1019 is D-methyl-LVFFL [34, 35].

Fig. (4)

The chemical structure of NH₂-D-Trp-Aib-OH [36].

Fig. (5)

Chemical structure of Ac-Aβ12-28P-Amid [37].

Fig. (6)

The chemical structure of D-4F [86].

Fig. (7)

Chemical structure of D3 [40].