Familial forms of Alzheimer’s disease: Investigation of the novel APPAros mutation and continued development of CRISPR-based gene therapy

We have found several amyloid precursor protein (APP) and presenilin 1 (PSEN1) mutations causing familial Alzheimer’s disease (fAD).

Such studies are central to the development of immuno- and gene therapies targeting amyloid-β (Aβ), the neurotoxic peptide cleaved from APP. We will now study yet another disease mutation, APPAros, located at the alternative β´ cleavage site.

Apart from exploring how the mutant affects APP cleavage, we will assess its aggregation properties and neurotoxic impact.We will also continue our development of gene editing as a therapy for fAD.

We showed that CRISPR/Cas9 can disrupt APP with the Swedish mutation (APPSwe) to counteract Aβ overproduction in APPSwe patient fibroblasts and reduce APP expression in brains of living mice.

By now targeting PSEN1M146L we explore if the Aβ isoform dysbalance and changed presenilin 1 conformation associated with this mutation can be restored in patient fibroblasts.

Moreover, with adeno-associated viral-vector based delivery we evaluate if systemic CRISPR/Cas9 treatment can ameliorate brain pathology and behavior in two APPSwe mouse models.Apart from investigating pathogenic effects of the recently discovered APPAros this program aims at further exploring CRISPR/Cas9 as a future gene therapy for fAD.

A CRISPR/Cas9-based clinical trial for systemic treatment of familial transthyretin amyloidosis was recently initiated, which implies that such a strategy could be feasible also for fAD.