Molecular Mechanisms in Alzheimer’s Disease

Luca Colnaghi, PhD
Istituto di Ricerche Farmacologiche Mario Negri (Milan, Italy)

Mentors

Luana Fioriti, PhD
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$180,000
Grant Reference ID:
A2019296F
Award Type:
Postdoctoral Fellowship
Award Region:
International
Luca Colnaghi, PhD

SUMOylation in Alzheimer's Disease and Dementia

Summary

Protein aggregation and deposition in the brain is a striking feature of several neurodegenerative disorders. This is particularly relevant to Alzheimer’s disease (AD), in which the abnormal increase of the protein tau and its aggregation are crucial steps in the chain of events leading to dementia. However, how cells modulate aggregation of these proteins is not clear. The goal of our project is therefore to define the molecular pathways involved in the aggregation of tau.

Details

To carry out the proposed project, I combine molecular biological and in vivo techniques. In aim1, I analyze the brain tissue of AD transgenic mice to define whether tau is post-translational modified. The analysis is carried out using mice at different ages, to determine how tau changes with the progression of the disorder. In aim2 and aim3, I better define the findings of aim1. Specifically, I study how the post-translational modifications of tau affect its biochemical properties and I define their contribution to the progression of AD. To accomplish this, I use a viral-based approach to inhibit the modifications of tau followed by in vitro and in vivo analysis.

The originality of our project stems from the focus of our analysis on still understudied post-translational modifications of tau. These modifications have already been described in patient-derived specimens but still lack a clear definition of their role in the pathology.

While the connection between tau toxicity, aggregation and neurodegeneration is widely accepted, it is still unclear how tau transitions from being soluble to being aggregated and pathogenic. Our aim is to define the molecular mechanism that may regulate this transition. Our project, therefore, has the potential to suggest novel pharmacological targets to reduce tau toxicity and therefore slow down or even arrest the progression of AD.

About the Researcher

Dr. Luca Colnaghi is a postdoctoral associate at the Mario Negri Institute in Milan, Italy. He received his PhD degree in cellular and molecular biology from NYU Langone Medical Center. Under the supervision of dr. Huang, he studied how post-translational modifications of the proteins FANCI and FANCD2 caused the Fanconi Anemia disorder. He next focused his attention on the molecular mechanism of memory, under the supervision of Dr. Eric Kandel. While working at Columbia University, he and his colleagues described how a physiological prion-like mechanism may be involved in memory persistence. Currently, he works on the molecular pathological aspects of learning and memory.

Personal Story

During high school, I became fascinated by the molecular processes that regulate our cells and influence our lives. I was particularly intrigued by the brain and how memory can form and be maintained in neurons. After obtaining my PhD, I was fortunate enough to work with Dr. Eric Kandel, a worldwide known expert in the memory field and one of the founders of modern neurobiology. Under his supervision, I started working in the fascinating field of memory but I soon realized that I was more interested in trying to understand the pathological aspects of memory. The realization came after seeing family members and friends develop age-related memory loss or dementia. Since then, I have investigated how molecular processes may cause Alzheimer's disease to provide new evidence for the development of new therapeutic targets. I am therefore really grateful to the donors of the BrightFocus Foundation for their support and for funding my research that I am convinced can help define understudied aspects of the disorder.

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