Study of the interplay between Herpes Simplex Virus 1 and the APOE4 lipoprotein in the onset of sporadic Alzheimer's disease: investigating the therapeutic potential of autophagy modulation
Abstract:
Alzheimer’s disease (AD) is the most common form of dementia, which nowadays affects 55 million people worldwide. In spite of huge research efforts, AD therapy is still a major unmet medical need. The animal models available recapitulate some of the features characterizing AD and contributed to a better understanding of the disease. However, the efficacy of treatment options developed using the current preclinical models failed the expectations when tested in humans. One possible reason for this translational failure may be that the available AD models mimic only genetic alterations found in familial cases, which represent 5% of the AD affected patients. On the contrary, nearly 95% of AD cases are sporadic, pointing to an urgent need to develop aetiology-based models of sporadic AD to identify novel therapeutic mechanisms with a translational utility.
The interaction of genetic and environmental factors that increase the risk of developing sporadic AD are still unknown. One of the most relevant genetic alleles associated with the development of late-onset AD is the E4 variant of the APOE lipoprotein. On the environmental side, recent evidence suggests that neurotropic viral infections may contribute to AD pathogenesis. In particular, the re-activation of latent infection with Herpes Simplex virus-1 (HSV-1) seems to play a role in triggering AD with unknown mechanisms. Interestingly, these two factors seem to converge at a molecular level on the autophagic pathway, whose dysfunction has extensively been linked to several neurodegenerative diseases.
Given these premises, our first aim is to combine the most common genetic risk factor (i.e., APOE4 allele) and an environmental trigger (i.e., HSV-1 infection) to generate novel in vitro and in vivo mouse models that more closely simulate the pathogenic cascades of sporadic AD. To do so, APOE4 knock-in mice and neuronal cultures will be infected with a replication-defective HSV-1 virus. These models will be characterized and validated for the presence of classical hallmarks of AD, such as amyloid-beta deposition, Tau hyperphosphorylation and cognitive alterations in vivo. These results will be systematically compared to those obtained in APOE4 KI mice using a canonical model of AD based on the central infusion of the oligomeric species of amyloid-beta.
Our second aim is to identify new targeting strategies that could be beneficial in sporadic AD. To this aim, the therapeutic potential of autophagy promoting drugs will be assessed in our models.
Considering that the worldwide social and economic burden of dementia is expected to increase exponentially in the next 20 years, the development of a sporadic AD model and the generation of novel anti-AD drugs represent an impactful breakthrough in the field. Our results will critically advance the mechanistic understanding of the disease and help to guide successful development of effective treatments in AD patients.
The interaction of genetic and environmental factors that increase the risk of developing sporadic AD are still unknown. One of the most relevant genetic alleles associated with the development of late-onset AD is the E4 variant of the APOE lipoprotein. On the environmental side, recent evidence suggests that neurotropic viral infections may contribute to AD pathogenesis. In particular, the re-activation of latent infection with Herpes Simplex virus-1 (HSV-1) seems to play a role in triggering AD with unknown mechanisms. Interestingly, these two factors seem to converge at a molecular level on the autophagic pathway, whose dysfunction has extensively been linked to several neurodegenerative diseases.
Given these premises, our first aim is to combine the most common genetic risk factor (i.e., APOE4 allele) and an environmental trigger (i.e., HSV-1 infection) to generate novel in vitro and in vivo mouse models that more closely simulate the pathogenic cascades of sporadic AD. To do so, APOE4 knock-in mice and neuronal cultures will be infected with a replication-defective HSV-1 virus. These models will be characterized and validated for the presence of classical hallmarks of AD, such as amyloid-beta deposition, Tau hyperphosphorylation and cognitive alterations in vivo. These results will be systematically compared to those obtained in APOE4 KI mice using a canonical model of AD based on the central infusion of the oligomeric species of amyloid-beta.
Our second aim is to identify new targeting strategies that could be beneficial in sporadic AD. To this aim, the therapeutic potential of autophagy promoting drugs will be assessed in our models.
Considering that the worldwide social and economic burden of dementia is expected to increase exponentially in the next 20 years, the development of a sporadic AD model and the generation of novel anti-AD drugs represent an impactful breakthrough in the field. Our results will critically advance the mechanistic understanding of the disease and help to guide successful development of effective treatments in AD patients.
Dettagli progetto:
Referente scientifico: Ruzza Chiara
Fonte di finanziamento: Bando PRIN 2022
Data di avvio: 16/10/2023
Data di fine: 16/10/2025
Contributo MUR: 70.175 €
Partner:
- Università degli Studi di FERRARA (capofila)
- Consiglio Nazionale delle Ricerche
- Università degli Studi di CAMERINO