Project Portugal 2030

Summary

In previous years, many efforts have been made to develop and repurpose Alzheimer’s disease (AD) pharmacological and immuno- therapies; the latter have recently gained much attention due to the possibility of decreasing Abeta brain levels as well as potentially demonstrating cognitive efficacy in some AD patients. However, neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy and thus investigating basic mechanisms occurring in early stages of AD and advancing the search for more effective therapies must continue, while there is also a large concern in the scientific community regarding the development of disease-progression biomarkers. A growing body of evidence indicates that epigenetic alterations linked to imbalance of activating and repressive histone modifications and transcriptional changes play a crucial role in aging and age-related diseases (e.g. Sen et al, 2016). These are particularly relevant in age-related brain diseases as AD, for which an increased number of senescent neurons, with compromised epigenetic signature, was reported in the brains of AD patients, and in AD induced-neurons transdifferentiated from human fibroblasts (Herdy et al, 2022). Furthermore, we recently showed increased levels of nuclear class I HDAC2/3 in AD postmortem brain samples from AD patients, peripheral blood mononuclear cells from AD prodromal cases diagnosed with mild cognitive impairment (MCI), APP/PS1 mouse brain, as well as in hippocampal cells subjected to oligomers of amyloid-beta peptide; in addition, we showed neuroprotective effects of class I HDACi and knock-down of HDACs 2 and 3 in AD models, namely by regulating the expression of proteins present at mitochondrial-associated membranes, establishing the link between ER and mitochondria (Marinho et al., 2023). Thus, in the current proposal we aim to investigate the impact of reducing the activity and/or expression of class I HDACs on AD-related senescence markers regulated by transcriptional modifications and the underlying transition to symptomatic disease. We will assess general senescence biomarkers and the role of mitochondrial deregulation, and further determine the influence of HDACi in postponing AD-related symptomatology concomitantly with brain senescence when applied at presymptomatic stage in an AD knock-in mouse model. For this purpose, three tasks will be delineated according to the following specific objectives: 1. Determine the role of HDACi on Abeta-induced senescence biomarkers and SASP phenotype (Task 1); 2. Examine the influence of HDACi on Abeta-induced mitochondrial deregulation and the crosstalk with DNA damage (Task 2) 3. Evaluate the role of HDACi in postponing AD-related symptomatology in AD knock-in mouse model by regulating transcription and senescence markers (Task 3) Reducing class I HDACs through pharmacological inhibition and/or selective knock-down is expected to ameliorate AD-related senescence phenotypes and delay the transition to AD-related symptomatology through the control of transcriptional activity, allowing to study the heterogeneity and dynamic changes of distinct brain cells. This is an innovative therapeutic approach towards the early and age-dependent biomarkers that later culminate in severe neuropathology and cognitive deterioration in AD.