| Abstract | dc.description.abstract | During the past few years, an increasing set of evidence has supported the major role of
deregulation of the interaction patterns between glial cells and neurons in the pathway toward
neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute
an integrated system for brain function. Inflammation is a process related with the onset of
several neurodegenerative disorders, including Alzheimer’s disease (AD). Several hypotheses
have been postulated to explain the pathogenesis of AD, but none provides insight into
the early events that trigger metabolic and cellular alterations in neuronal degeneration.
The amyloid hypothesis was sustained on the basis that Ab-peptide deposition into senile
plaques is responsible for neurodegeneration. However, recent findings point to Ab oligomers
as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one
among many other major factors affecting the quality of neuronal cells. Another explanation
derives from the tau hypothesis, supported by the observations that tau hyperphosphorylations
constitute a common feature of most of the altered signaling pathways in
degenerating neurons. Altered tau patterns have been detected in the cerebrospinal fluids
of AD patients, and a close correlation was observed between the levels of hyperphosphorylated
tau isoforms and the degree of cognitive impairment. On the other hand, the
anomalous effects of cytokines and trophic factors share in common the activation of
tau hyperphosphorylation patterns. In this context, a neuroimmunological approach to
AD becomes relevant. When glial cells that normally provide neurotrophic factors essential
for neurogenesis are activated by a set of stressing events, they overproduce cytokines and
NGF, thus triggering altered signaling patterns in the etiopathogenesis of AD. A solid set of
discoveries has strengthened the idea that altered patterns in the glia-neuron interactions
constitute early molecular events within the cascade of cellular signals that lead to neurodegeneration
in AD. A direct correlation has been established between the Ab-induced
neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation
is responsible for an abnormal secretion of proinflammatory cytokines that
trigger signaling pathways that activate brain tau hyperphosphorylation in residues that
are not modified under normal physiological conditions. Other cytokines such as IL-3
and TNF-a seem to display neuroprotective activities. Elucidation of the events that control
the transitions from neuroprotection to neurodegeneration should be a critical point toward
elucidation of AD pathogenesis. | en_US |
