ADMIR: Systematic assessment of microRNA-132 supplementation to treat Alzheimer’s disease

Here, we proposed a strategic partnership between academia and pharmaceutical industry, i.e. the Netherlands Institute for Neuroscience and Janssen Pharmaceutica, focused on generating innovative therapeutics for the treatment of Alzheimer’s disease (AD). Our aim was to systematically test the suitability of microRNA-132 as a therapeutic target for AD. 

By 2040, dementia patients in the Netherlands will double, reaching approximately 500.000, while there will be an estimated 130.000.000 dementia patients worldwide by 2050. AD comprises 50-75% of all dementia cases. AD cannot be currently prevented, slowed down or cured, being one of the main causes of disability later in life, ahead of cancer, cardiovascular disease and stroke. Ameliorating pathology can substantially improve life quality of patients, their families and care givers, while it will also reduce the cost of social care expected to triple by 2040. AD is a complex, multifactorial disorder: all clinical trials have failed this far, mainly because of targeting only one single molecule or pathway along with inadequate preclinical validation. 

In this collaborative project, we systematically assessed the therapeutic potential and safety of a microRNA-based strategy for AD treatment. microRNAs are small endogenous molecules that control all functions in our cells, including the cells of our brain. Using novel animal and cell models and developing innovative tools for non-invasive brain delivery, we validated microRNA supplementation as a novel therapeutic approach to tackle AD complexity. More specifically, we initially proposed that increasing the levels of microRNA-132 (a microRNA regulating several physiological brain functions and decreasing in human AD brain) in AD brain, can restore multiple aberrant cellular and molecular processes, and thereby improve memory deficits. As indicated below, our results confirmed our hypothesis and further solidified miR-132 as a potential novel therapeutic target for AD. 

Our research has achieved the following general objectives: A. identified the complex mechanisms of microRNA-132 function in healthy and AD brain, B. developed novel tools for non-invasive delivery of RNA-based therapeutics into the brain, and, C. systematically addressed the functional effects, safety and thereby suitability of microRNA-132 as a target for further drug development in AD. 

More specifically: 

-We identified a novel role for miR-132 in brain inflammation (neuroinflammation), which could have implications for its putative use as therapeutic target in AD, via previously unknown protective effects.  

-We optimized a brain delivery system for miR-132 that specifically targets neurons (major brain cell population) and has the potential to be used intravenously, so a potential non-invasive delivery system. This system could be used in future preclinical studies.  

-We identified a safe dose for supplementing miR-132 levels in AD brain (where miR-132 levels are reduced), which can be used as a starting point for follow-up preclinical studies.