Diabetes-associated systemic inflammation and Alzheimer disease progression from preclinical to clinical stage: from complex models to single cell level

Acronimo:

Alzheimer disease (AD) is a still uncurable, devasting disease, whose pathological mechanisms are not fully understood. Based on the genetic of early-onset, familiar form, altered amyloid biochemical processing is still in the core of pathogenetic hypothesis, but

the emerging vision refers to the very long preclinical history of the disease in both early onset, familiar and late onset, sporadic AD.

According to this, life-style factors, such as comorbidities, environmental factors etc. occurring in “at risk” individuals could worsen pathogenic mechanism anticipating symptoms appearance. While neuroinflammation is considered a co-factor in precipitating

amyloid pathology, the possible role of systemic inflammation associated to many diseases showing epidemiological links to mild cognitive impairment and AD is still obscure.

This proposal aims to explore the possible causal link between chronic systemic inflammation occurring during the preclinical, asymptomatic phase of AD, amyloid dysfunction, and acceleration of cognitive decline. The proposal will investigate specific, but still poorly explored aspects of cellular and molecular effects of systemic inflammation having potential implications for amyloid protein processing.

As inflammation challenges, we will investigate diabetes, a major co-factor in sporadic AD, characterized by systemic, chronic inflammation due to both peripheral insulin resistance and defective pancreatic islet β-cell insulin secretion.

The project is organized into three major activities, and adopts a “reverse-engineering” approach, starting from complex system (human samples from a clinical blood bank of cognitive impaired patients + diabetes, and diabetes induced in a murine AD model),

then moving to more simplified in vitro systems (brain organotypic slices and mixed cortical or brain primary cells derived from pathological animals), until pure and/or modified cells to investigate specific pathways.

At the end of the project, we aim to:

• identify peripheral mediators of systemic inflammation due to diabetes linked to the onset of neurological symptoms and amyloid dysfunction in “at risk” subjects, to be used also as “biomarkers”;
• identify the peripheral cytokine mix in diabetes that triggers/exacerbates the dysfunction of intracellular amyloid peptide processing among the above identified biomarkers in “at risk” condition;
• identify the cell type in the neurovascular unit (brain capillary endothelial cells, neurons, astrocytes), that triggers amyloid dysfunction;
• establish if a mechanistic link between inflammatory molecules and intracellular amyloid processing exists in diabetic AD mice.