| Abstract | dc.description.abstract | The idea that alterations in the brain immunomodulation are critical for Alzheimer’s
disease (AD) pathogenesis provides the most integrative view on this cognitive disorder,
considering that converging research lines have revealed the involvement of inflammatory
processes in AD. We have proposed the damage signal hypothesis as a unifying
scheme in that release of endogenous damage/alarm signals, in response to accumulated
cell distress (dyslipidemia, vascular insults, head injury, oxidative stress, iron
overload, folate deficiency), is the earliest triggering event in AD, leading to activation
of innate immunity and the inflammatory cascade. Inflammatory cytokines play
a dual role, either promoting neurodegeneration or neuroprotection. This equilibrium
is shifted toward the neurodegenerative phenotype upon the action of several risk factors
that trigger innate damage signals that activatemicroglia and the release of tumor
necrosis factor-α, interleukin-6, and some trophic factors. In this neuroimmunomodulatory
hypothesis we integrate different risk factors withmicroaglial activation and the
resulting neuronal alterations and hyperphosphorylations of tau protein. The progression
of AD, with slowly increasing damage in brain parenchyma preceding the onset
of symptoms, suggests that tissue distress triggering damage signals drives neuroinflammation.
These signals via toll-like receptors, receptors for highly glycosylated end
products, or other glial receptors activate sensors of the native immune system, inducing
the anomalous release of cytokines and promoting the neurodegenerative cascade,
a hallmark of brain damage that correlates with cognitive decline. | en_US |
