Liquoral and plasmatic markers of synaptic degeneration in cognitive decline: a validation in the clinical practices and in animal models

Cognitive decline is the main feature of brain aging. The stringent importance of the problems resulting from neurodegeneration is evidenced by the fact that mild cognitive impairment (MCI) and Alzheimer disease (AD) currently affects over 10 million Europeans, and that these diseases are set to double or triple by 2050 within the aging population (Wancata et al., 2003). It is believed that an age-related neurodegeneration sustains MCI and AD. Indeed, a neuronal loss with the presence of betaamyloid plaques, neurofibrillary tangles, (whose main constituent is a protein tau, in a hyperphosphorylated state) (Golde, 2005), inflammation and synaptic alterations affects the cerebral cortex, the amygdala, the entorhinal cortex and the hippocampus. However, cognitive signs and brain changes are subtly present prior to clinical diagnosis, thus denoting a "preclinical" stage, in which aged individuals exhibit only very mild changes in cognition despite the process of the disease being ongoing (Selkoe and Schenk, 2003). Interestingly, in the initial phases of cognitive decline, there are no obvious signs of cell death, but there is a lack of communication between neurons at the synaptic level that persists throughout all the phases of mental impairment. Therefore, a synaptic dysfunction would be primarily responsible for the onset and maintenance of the cognitive decay. It is not defined yet, how synaptic alteration and neuronal degeneration occur. It has been suggested that beta- amyloid activates caspases, a key step in the programmed cell death pathway. The activated caspases can in turn cleave tau, the main component of neurofibrillary tangles. Thus, caspase-cleaved tau (delta-tau) may initiate or accelerate the development of tangle pathology (for a review see Cotmann et al., 2005). These studies suggest caspase cleavage of tau provides a mechanistic link between the development of amyloid and tangle pathologies. Accordingly, a localized caspase-dependent apoptosis-like mechanism (termed "synaptosis") is thought to contribute to early synaptic loss leading to the initial cognitive decline.