04:20pm Sunday 12 July 2020

Exploring the process of physiological brain aging

The brain is such a complex organ. Why did you think that phosphoinositide would be involved in brain dysfunction during aging?
Carlos: The rationale behind this choice arose as consequence of previous work from my group, showing that lipid dyshomeostasis is a major event accompanying aging, as well as from work of others, showing that phosphoinositides are key modulators of synaptic plasticity.


Your results confirm that a loss in synaptic MARCKS during aging is responsible for the impairment of certain aspects of neuronal function. Can you explain?
Laura: Our data suggest that part of the cognitive loss that accompanies aging is a consequence of a reduced association to the plasma membrane of the cholesterol-binding and actin-regulatory molecule MARCKS in the synapses of the hippocampus. This in turn leads to reduced clustering of the phosphoinositide PI(4,5)P2 for hydrolysis by PLCɣ and consequently in a reduced signaling towards the expression of learning and memory genes.


In support of the conclusion that the loss of MARCKS is an important determinant of cognitive decay during aging, we showed that MARCKS replenishment in the hippocampus of old mice improves synaptic plasticity at three different levels: biochemical, electrophysiological and behavioral. We speculate that an exaggeration of this mechanism may contribute to the appearance of signs of pathological aging.



Carlos Dotti (bottom row, first from the left) & Laura Trovò (middle row, fourth from the left)


What is the impact of this study?
Carlos: For the moment it is just academic: we learnt about one of the molecular events participating in a particular deficit of the old: reduced hippocampal synaptic plasticity. It remains to be established whether or not an exaggeration of the biochemical deficits discovered in our work (eg. MARCKS/PIP2 loss), or an earlier occurrence of this deficit, plays a role in pathological brain aging.



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