Role of NLRP3 Inflammasome in Alzheimer’s Disease

Review Article

Austin J Clin Neurol 2015;2(3): 1029.

Role of NLRP3 Inflammasome in Alzheimer’s Disease

Khan S1, Hashmet Parveen Ghouse1 and Fatima- Shad K2*

1Institute of Biomedical Sciences, University Brunei Darussalam, Brunei

2School of Medical and Molecular Biosciences, University of Technology Sydney (UTS), Australia

*Corresponding author: Fatima-Shad K, School of Medical and Molecular Biosciences, University of Technology, Sydney, 15 Broadway, NSW 2007, Australia

Received: March 15, 2015; Accepted: March 31, 2015; Published: April 09, 2015


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in elderly. Amyloid beta (Aβ) aggregation and its association with specific receptors on microglia initiate chronic inflammatory response.

Nod like receptor family pyrin domain containing 3 gene (NLRP3) member of family of pattern recognition receptors (PRRs) initiate inflammation and apoptosis. NLPR3 inflammasome is a multiprotein complex and part of innate immune system. Injury induced activation of NLRP3 inflammasome via recognition of danger Associated molecular patterns (DAMPs) facilitate inflammasome complex formation and maturation of pro-IL-1β (and pro- IL-18) through caspases-1 and exacerbate the pathological condition by neuroinflammation. A review of the data shows that activation or inhibition of NLRP3 inflammasome leads to changes in process of neuroinflammation which may influence maturation and release of pro-IL-1β (and pro-IL-18) and Aβ accumulation and result in AD pathogenesis.

Keywords: Alzheimer’s disease; Amyloid β; NLPR3 inflammasome; Neuroinflammation; Microglia


Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disorder of elderly population [1]. The presence of two molecules extracellular Aβ in form of senile plaque and intracellular neurofibrillary tangle are characteristic feature of AD pathologies. In general, AD is associated with synaptic dysfunction, loss of neuronal circuits and networks [2]. However, the cause and subsequent development of pathologies of AD is still only partially understood, a number of genetic factors such as gene mutation, allelic variants all have been link to AD incidence. Furthermore, environmental factors also have influence on risk of AD development including exposure to metals their metabolism related to mitochondrial dysfunction, ROS production and apoptosis.

Both familiar and sporadic forms of AD share almost similar pathophysiology; Aβ accumulation, tau hyperphosphorylation and impaired axonal transport. These pathologic events cause toxic damage to cellular organelles resultant in ROS production and oxidative stress [3].

Aβ accumulation initiates an immune response by activating brain resident immune cells called “Microglia”. These microglias have specific receptors on their surface. Aβ peptide can activate these receptors. Activation of these receptors on microglia-mediate neuroinflammatory response [4,5]. Neuroinflammation is crucially associated with AD pathogenesis. It is further exacerbate the pathological condition and generate a plethora of inflammatory mediators and neurotoxic compounds. Inflammatory response in AD is initiated by Pattern recognition receptors (PRRs) (which are an integral part of immune system) recognize pathogen associate molecular patterns (PAMPs) and damage associated proteins (DAMPs) on glial cells, macrophages and oligodendrocytes within the brain. They can be membrane bound (toll-like receptors) or within the cytoplasm [Nod-like receptors (NLRs)]. NLRPs activation leads to assembly and activation of multiprotein complex known “inflammasome”. This inflammasome activation enables activation of pro-inflammatory caspases, particularly caspase-1. This then lead to activation and maturation of interleukin (IL)-1β, IL-18, and IL-33 [6,7].

Neuronal injury caused by insoluble Aβ peptide and tau tangle releases DAMPs which are recognized by PRRs (NLR domain) present in NLRP inflammasome initiate cascade of events leading to maturation and release of pro IL-1β, IL-18. Additionally, Aβ interaction with neuronal membrane cause efflux of K+ ions by forming ions channels, activates inflammasome which in turn secretion of cytokines. Purinergic P2X7 receptor activation decreases intracellular K+ levels. Impaired activity of Na+/K+ ATPase reduces ions gradients across the cell membrane cause cytotoxicity resulting neuronal cell death. Neuronal death serves danger signal by releasing DAMPs to activate NLRP3 inflammasome (Rubartelli, 2014). In addition with Aβ aggregation or protein misfolding and mitochondrial ROS give signal to NLRP3 inflammasome activation and up regulating pro inflammatory cytokines levels in brain resultant neuroinflammation [8].

Deficiency of NLRP3 inflammasome largely protects brain from deleterious effect of neuroinflammation. It is assuming that microglia-specific inflammasome as a promising cell type-specific molecular target in the CNS for therapeutic intervention for AD.

NLRs Structural Organization

There are 23 NLRs have been studied in human divided into four subfamily, Table 1 Most NLRs contain, nucleotide binding and oligomerization (NACHT) domain activates signaling pathways for proinflammatory cytokines. The C terminal contain leucine- rich repeat (LRRs) and an N terminal caspase and recruitment domain (CARD) or pyrin domain (PYD) as effector binding domain [9].