The Tat-Aβ1-6A2V(D) peptide against AD synaptopathy

Synaptopathy is an increasingly popular term used to define a cellular event occurring in an early stage of many neurodegenerative, neurodevelopmental and psychiatric disorders. Such synaptic dysfunction is closely related to cognitive impairment. Nowadays, it is assumed that neurodegenerative diseases, including Alzheimer’s disease (AD), are synapse-related pathologies (defined as “synaptopathy”) in which misfolded proteins lead to synaptic dysfunction and loss, an event that precedes extensive aggregation of proteins (such as Aβ-oligomers, Phospho-Tau and synuclein) in the brain parenchyma. However, the relationship between protein aggregation and synapses loss remains unclear. Among brain diseases, AD synaptopathy, occurring at a very early stage of the pathology and it is clearly detectable already in patients with mild cognitive impairment (MCI), is the most studied. The spine-pathology represents a key event of this disease and offer an intriguing possibility to tackle AD. According to the amyloidogenesis hypothesis, altered Aβ species are the primary cause of spine dysfunction and find a way to prevent Aβ toxicity represents an important target for therapeutic intervention against synaptopathy. Recently, clinical observations have shown that a human mutation in the APP protein (A673V mutation) induces an early onset AD-type dementia in homozygous carriers, while heterozygous carriers are unaffected [1]. In the homozygous patients for A673V mutation, Aβ species were mutated and the APP cleavage generated Aβ mutated oligomers (Aβ1-42A2V), while in heterozygous the Aβ oligomers were a mix of both Aβ1-42 wildtype and Aβ1-42A2V mutated species. To better understand the impact of the A673V mutation in AD, we analyzed the synapto-toxic effect of oligomers formed by the aggregation of different Aβ peptides: 1) the wildtype Aβ142 wt, 2) the mutated Aβ1-42A2V and 3) the combination of the two species: Aβ1-42MIX (Aβ1-42wt and Aβ1-42A2V) in a well characterized in vitro model of synaptopathy [2]. We proved that Aβ1-42A2V is more toxic than Aβ1-42wt oligomers and induce a more severe synaptic injury in hippocampal neurons. This result is in agreement with the human pathology of the AD A673V-homozygous carriers. Interestingly, the combination of wild type and mutated peptides (Aβ1-42MIX) did not exert any synaptic toxicity, confirming that the combination of both species, Aβ1-42 wt and Aβ1-42A2V peptides, hinders the Aβ-induced-toxicity