Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

Abstract

Inflammatory mechanisms are implicated in the pathology of Alzheimer’s disease (AD). However, it is unclear whether inflammatory alterations are a cause or consequence of neurodegeneration leading to dementia. Clarifying this issue would provide valuable insight into the early diagnosis and therapeutic management of AD. To address this, we compared the mRNA expression profiles of cytokines in the brains of AD patients with “non-demented individuals with AD pathology” and non-demented healthy control (ND) individuals. “Non-demented individuals with AD pathology” are referred to as high pathology control (HPC) individuals that are considered an intermediate subset between AD and ND. HPC represents a transition between normal aging and early stage of AD, and therefore, is useful for determining whether neuroinflammation is a cause or consequence of AD pathology. We observed that immunological conditions that produce cytokines in the HPC brain were more representative of ND than AD. To validate these result, we investigated the expression of inflammatory mediators at the protein level in postmortem brain tissues. We examined the protein expression of tumor necrosis factor (TNF)α and its receptors (TNFRs) in the brains of AD, HPC, and ND individuals. We found differences in soluble TNFα and TNFRs expression between AD and ND groups and between AD and HPC groups. Expression in the temporal cortex was lower in the AD brains than HPC and ND. Our findings indicate that alterations in immunological conditions involving TNFR-mediated signaling are not the primary events initiating AD pathology, such as amyloid plaques and tangle formation. These may be early events occurring along with synaptic and neuronal changes or later events caused by these changes. In this review, we emphasize that elucidating the temporal expression of TNFα signaling molecules during AD is important to understand the selective tuning of these pathways required to develop effective therapeutic strategies for AD.

The immune system on the TRAIL of Alzheimer’s disease

“…In light of the fact that increased exchange of immunocytes may occur between peripheral lymphoid organs and the brain [135], it is noteworthy that the integrity of the BBB may not necessarily subsists in course of neurodegenerative disorders [136]. In fact, peripheral immunocytes have been indicated as factors that, when the inflammatory/immune equilibrium within the CNS is disrupted, are able to significantly influence progression of the AD brain pathology [74,137]. Now, considering the pleiotropic role of TRAIL in orchestrating key events of the inflammatory/immune response, it appears of interest how its immunoneutralization also leads to a rebalance of immunocytes ratios, with special regard to the Treg cell population either in the spleen and in the brain [18].…”

“…In light of the fact that increased exchange of immunocytes may occur between peripheral lymphoid organs and the brain [ 135 ], it is noteworthy that the integrity of the BBB may not necessarily subsists in course of neurodegenerative disorders [ 136 ]. In fact, peripheral immunocytes have been indicated as factors that, when the inflammatory/immune equilibrium within the CNS is disrupted, are able to significantly influence progression of the AD brain pathology [ 74 , 137 ].…”

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

“…Magaki et al ( 2007 ) showed that alteration in cytokines through peripheral blood mononuclear cells (PBMCs) might be detected early in mild cognitive impairment. Additionally, other studies have been done on the role of cytokines in AD, cognitive impairment, and neurological disorders (Aarli, 2005 ; Nagae and Araki, 2016 ). Chang et al ( 2012 ) discussed that p53 interacts with cellular factors, viral factors, and small RNAs, explaining its role in the development of neurodegenerative diseases.…”

Protective effect of ISO‑1 against advanced glycation end product aggravation of PC12 cell injury induced by Aβ1‑40

“…Hippocampal neuronal injury is an important component of AD pathology and is closely related to the occurrence of neuritis, the deposition of Aβ and the hyperphosphorylation of tau proteins (27). A previous study into the causal relationship between neuroinflammation and AD reported that neuroinflammation may be involved in the pathogenesis of AD, and that an increase in the levels neuroinflammatory mediators was observed in AD (28). Thus, neuroinflammation serves an important role in the development of AD.…”