At the Crossroad between Neuronal Hyperexcitability and Neuroinflammation: New Therapeutic Opportunities for Alzheimer’s Disease?
Pp. 192-226 (35)
Chelsea Cavanagh and Slavica Krantic
Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease.
Clinically available treatments, such as cholinesterase inhibitors, are based mainly on
the cholinergic hypothesis of AD. These treatments, as well as those targeting the
NMDA type of glutamate receptors all provide only a limited therapeutic benefit. The
field of AD research has also shifted focus to develop intervention strategies that
prevent overt symptoms, such as amyloid plaque deposition and memory loss, in
agreement with the more recent amyloid hypothesis of AD. However, to date, all
amyloid-directed therapeutics for the treatment of AD have failed, suggesting that
additional factors may be involved in the etiology of the disease and mobilizing the search for additional drug targets. By studying the early stages of AD, candidate drug
targets (e.g. cytokines or neuronal network activity) have been identified and are now
at advanced stages of preclinical development. Throughout this chapter we will focus
on two aspects of AD that have garnered widespread attention with respect to future
therapeutic intervention strategies. First, a common feature of both mouse models of
AD and patients with the disease is hyperexcitability at the level of the synapse as well
as neuronal networks. New research is starting to uncover the causes of this
hyperexcitability and which cell types are vulnerable, thus, providing attractive
therapeutic targets. Second, AD brains are affected by neuroinflammation-like
alterations at early stages, which turn into overt neuroinflammation at the late stages.
Reducing this activity by targeting the proinflammatory cytokine, tumor necrosis
factor-α (TNFα), is thought to be a promising strategy to treat AD. Furthermore, given
the cross-talk between the nervous system and the immune system, we hypothesize that
the hyperexcitability and progressive induction of neuroinflammation may be related.
Here, we summarize studies in both animal models of AD and AD patients related to
hyperexcitability and neuroinflammation in the early stages of the disease. Finally, we
propose that a combination treatment targeting these factors in addition to the amyloid
burden would be a possible way to target more facets of AD.
Alzheimer’s disease, Amyloid, Hyperexcitability, Inflammation,
Intervention, Prodromal, Synaptic, TNFα.
Sorbonne Universites, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche, des Cordeliers, F-75006, Paris, France.