The aging brain, a key target for the future: The protein kinase C involvement

Abstract

The brain represents the primary centre for the regulation and control of all our body activities, receiving and interpreting sensory impulses and transmitting information to the periphery. Most importantly, it is also the seat of consciousness, thought, emotion and especially memory, being in fact able to encode, store and recall any information. Memory is really what makes possible so many of our complex cognitive functions, including communication and learning, and surely without memory, life would lose all of its glamour and purpose. Age-associated mental impairment can range in severity from forgetfulness at the border with pathology to dementia, such as in Alzheimer's disease. In recent years, one of the most relevant observations of research on brain aging relates to data indicating that age-related cognitive decline is not only due to neuronal loss, as previously thought; instead, scientists now believe that age-associated functional changes have more to do with the dysfunctions occurring over time. Within this context a prominent role is certainly played by signal transduction cascades which guarantee neuronal cell to elaborate coordinated responses to the multiple signals coming from the outside and to adapt itself to the environmental changes and requests. This review will focus the attention on protein kinase C pathway, with a particular interest on its activation process, and on the role of protein–lipid and protein–protein interactions to selectively localize the cellular responses. Furthermore, information is emerging and will be discussed on the possibility of mRNA stabilization through PKC activation. This review will also approach the issue on how alterations of these molecular cascades may have implications in physiological and pathological brain aging, such as Alzheimer's disease.

Introduction

In recent years science and technology have made big steps, allowing us to greatly improve knowledge in basically every aspect of biology, culminating in the mapping of the human genome. However, although the brain is considered our most vital organ, the essence of personality and memory, much about the human brain still remains a mystery. Up to the second half of the 80s, neuroscientists thought that the brain was inexorably losing neurons with age, ultimately leading to serious cognitive deficits. In fact, morphological analyses seemed to support the idea that senescence was accompanied by neuronal loss, particularly evident in the cortical and hippocampal structures [1]. The remaining neurons compensated this deficit through an increased dendritic sprouting, at least until the degeneration did not exceed a certain threshold [2]. However, investigations based on stereological techniques, suggested that neuronal loss was much less important than what was previously believed [3]. Within this context, the finding that old rats, showing a reduced performance in the Morris maze spatial task, do not present any hippocampal (the hippocampus is the brain area mainly implicated in spatial orientation) neurodegeneration [4] further supports the concept that the cognitive decline that occurs with normal aging may be rather due to functional changes, such as those involving cell-to-cell communication and signal transduction mechanisms [5], [6]. Along with this idea, a growing number of observations indicates that age-associated alterations involve a broad spectrum of neurotransmitter systems and their related signalling pathways [7], [8], [9], [10]. Overall, these changes are responsible for an altered interneuronal communication that can represent, rather than morphological modifications, the primum movens leading to cognitive decline. Considering that protein kinases play a strategic role aimed to convert the extracellular signals into biological responses, it is logic to hypothesize that functional alterations on kinases may directly contribute to age-dependent neuronal dysfunctions. At brain level, among the different protein kinases, and especially for its key involvement in memory processes, a great interest has always been addressed to protein kinase C (PKC).