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Neuroimmunol Neuroinflammation 2019;6:15 I http://dx.doi.org/10.20517/2347-8659.2019.019 Page 5 of 24

including the maturation of two major pro-inflammatory cytokines, interleukin-1β (IL-1β) and
interleukin-18. Increased IL-1β, a member of the IL-1 cytokine family, has been implicated in the response
to Aβ deposition and up-regulated in specimens from patients with AD. Since IL-1β secretion is critically
dependent on the activation of inflammasomes, inflammasomes have been inferred as the missing link for
Aβ-induced IL-1β secretions.

Within the central nervous system (CNS), several types of inflammasome have been identified, of which
the best characterised are the absent in melanoma 2, NOD-like receptor (NLR)-family pyrin domain-
containing 1 (NLRP1), NLRP3 and NLR-family caspase recruitment domain (CARD)-containing 4
inflammasomes. Different subsets of inflammasomes contain different cytosolic pattern-recognition
receptors and their assembly is initiated by different stimuli. Once activated, inflammasome induces an
inflammatory cell death mode termed as pyroptosis. Pyroptosis is a process of programmed cell death
closely associated with inflammasome activation. However, in contrast to apoptosis, in pyroptotic cell,
the integrity of the cell membrane is affected and micro-pores are formed resulting in intracellular
and extracellular ion imbalance cell swelling and rupture. Meanwhile, the pro-inflammatory cytokines
are released to the extracellular space causing focal inflammation and cell death. Multiple potential
targets upstream of pyroptosis signaling may pave the way for newly therapeutic drugs that may rescue
inflammation in neurological diseases. This has incited us to study the response of human neurons to Aβ
and to determine whether specific neuronal molecular events initiated link neuronal degeneration to an
inflammatory response.

In our studies, Aβ was found to induce inflammasome activation and inflammasome-mediated
pyroptosis. Using gene-trap mutagenesis approach, candidate genes, which could play an important
role in regulating inflammasome-mediated pyroptosis have been identified. We also demonstrated that
neural stem cells (NSCs) regulated the NLRP3 inflammasome, and inhibited the production of IL-1β and
caspase-1 in activated microglia, as well as subsequently attenuating neurotoxicity caused by microglial
neuroinflammation, adding to the inherent benefits of NSCs in AD treatment. By understanding precisely
how inflammasomes work in the CNS under both physiological and pathological conditions, as well as
determining how these inflammasomes can be pharmacologically targeted, we may be one major step
closer towards developing a proper cure for AD.

7. Colocalization of iron and aluminum in nuclei of nerve cells in brains of patients with
sporadic Alzheimer’s disease

Sakae Yumoto

Tokyo University School of Medicine, Japan

The etiology of Alzheimer’s disease (sporadic Alzheimer’s disease, AD) remains to be clarified. However,
growing lines of evidence indicate that metal-induced oxidative stress plays a key role in the pathogenesis
[1]
of AD . Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage,
was demonstrated in nuclear DNA (nDNA) in the AD brain. It has also been reported that accumulation
of DNA damage is one of the earliest detectable events during the progression from healthy aging to
dementia.

Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA through
Fenton reaction. Aluminum (Al) has been reported to facilitate Fe-mediated Fenton reaction, as shown in
the chemical formulae below. These cyclic reactions continuously generate hydroxyl radicals and can cause
severe oxidative damage to nDNA.