Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid-β

Abstract

We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

Self-assembly of the full-length amyloid Aβ42 protein in dimers

“…66,67 Our simulations show a good correlation with experimentally data providing additional support for the use if this field amyloid type proteins. Recently, the ff99IDPs has been developed for IDP monomer simulation and demonstrate the good consistency with NMR data.…”

Translational Research in Alzheimer’s and Prion Diseases

“…The discovery of protective genetic variants like Aβ A2V and Aβ A2T , although rare, should prompt a novel vision of genetic studies, until now limited to the identification of pathogenic variants, expanding the genetic research into the detection of ‘protective’ DNA variations as useful grounds for the design of efficient disease-modifying therapies inmedicine [ 51 ].…”

“…CD spectroscopy, SPR, and AFM showed that Aβ1-6 A2V inhibits acquisition of β-sheet secondary structure by full-length wt Aβ, elongation of wt Aβ amyloid fibrils and assembly of Aβ into amyloid fibrils, dramatically reducing the formation of protofibrils and filamentous structures[ 35, 51 ]. Moreover, toxicity studies on cellular models showed that Aβ1-6 A2V is not toxic on SY-SH5Y neuroblastoma cells even at high concentrations (20μM) and hampers the toxicity induced by Aβ1-42 wt on these cells [ 51 ]. Finally, to improve the translocation across the blood-brain barrier (BBB), we linked an amino acid sequence highly rich in basic residues (TAT) to the six-mer peptide so generating the Aβ1-6 A2V -TAT(D) compound.…”

“…Short-term treatment (2.5 months) resulted in the exciting prevention of cognitive deterioration, Aβ production/aggregation and amyloid deposition in the brain. However, the final outcome (5 months after the beginning of treatment) consisted of an unexpected increase of amyloid burden and attenuation of the effects on Aβ production, while the prevention of cognitive impairment was maintained and even more evident [ 51 ]. Concomitant studies performed in our labs revealed a great propensity of TAT(D) to target amyloid deposits.…”

“…So, regardless its optimal BBB delivery abilities and cell penetrating activity [ 56 ], the design of therapeutic strategies for AD [ 57 ] should, in our opinion, take in account some intrinsic properties of TAT sequence, which can promote or worsen amyloidogenesis in long treatment schedules [ 51 ].…”