Highlights
- •Activation of microglia is one of the early events of the AD.
- •Modulation of microglia activation in the early stage is the best therapeutic approached to reverse AD progression.
- •Suppressing neuroinflammation by inhibiting activation of NF-kB signalling and P2X7/NLRP 3 pathways.
- •Purinoreceptor (P2X7) antagonist could be an important therapeutic target, especially in a neuroinflammation induced AD in the early stage.
Abstract
Microglial activation is a distinguished attribute in many neurodegenerative diseases
of aging. Compelling evidence suggests that neuroinflammation stimulated by microglia,
the resident macrophage-like immune cells in the brain, play a contributing role in
the pathogenesis of Alzheimer's disease (AD). Postmortem brain tissue of individuals
with AD has credibly demonstrated that neuroinflammation is likely to be a key driver
of the disease. Recently, It has been found that manipulating β-amyloid directly is
an impracticable approach for therapeutic intervention due to the failure of β-amyloid-lowering
drugs in clinical trials. Further, Current treatments relieve only symptoms and modestly
improve disease condition but do not reverse or prevent disease. Therefore, Inhibition
of microglia activation is effective strategies against the multifactorial and complex
AD. More recently there has been a center of attention on converting microglia from
this classic state to an alternate state in which the noxious effects are reduced
and their phagocytic action toward Aβ improved. The nuclear factor-kappa B (NF- kB)
and NLRP3 inflammasome activation by P2X7/NLRP3/caspase 1 pathways are closely linked
to Alzheimer’s disease (AD) via neuroinflammation, therefore it could be a rational
strategy to target these proteins to counteract the AD pathology. These strategies
could work effectively if therapeutic intervention started at an early stage. This
review highlights the potentials of drugs acting on the P2X7 receptor and its downstream
protein targets for inhibition of neuroinflammation. Thus it might act as a futuristic
strategy to treat Alzheimer’s disease.
Graphical abstract
Graphical Abstract
Keyword
Abbreviations:
NLRP3 (NOD like receptor protein 3), ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), ATP (adenosine triphosphate), CARD (caspase recruitment domain), DAMPS (danger or damage associated molecular patterns), IL (interleukin), LRR (leucine-rich repeat), NACHT (central nucleotide-binding and oligomerization), NF-κB (nuclear factor kappa B), P2X7 (P2X purinergic receptor 7), PAMPS (pathogen associated molecular patterns), PYD (pyrin domain), TLR (Toll-like receptor), MD2 (Muramyl dipeptide)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: November 20, 2018
Accepted:
November 18,
2018
Received in revised form:
November 16,
2018
Received:
August 8,
2018
Identification
Copyright
© 2018 Elsevier B.V. All rights reserved.
