Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimer's 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.

Keywords: Alzheimer’s disease; Cytokines; Neuroinflammation; Postmortem brain tissues; TNF receptors; Tumor necrosis factor (TNF)α.

Figure 1

TNFα protein levels in the temporal cortex and cerebellum of the AD, HPC and ND Brain. (A) Representative images of soluble TNFα (sTNFα) and transmembrane TNFα (mTNFα) protein bands at approximately 26 kDa and 17 kDa, respectively, from Western blots. T: Temporal cortex; C: Cerebellum; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase. (B) Densitometry analysis of sTNFα and mTNFα protein expression in the AD, HPC and ND brain. Data on the protein levels of sTNFα and mTNFα were normalized to GAPDH. Subsequently, the normalized data of AD and HPC groups were compared with ND group, and expressed as relative expression levels, where the data on ND were set as 100%. Values are expressed as the mean ± S.D. of the relative expression levels. n=5, *p<0.05 by Kruskal-Wallis non-parametric analysis with Steel-Dwass post-testing.

Figure 2

Protein levels of TNFR1 and TNFR2 in the temporal cortex and cerebellum of the AD, HPC and ND brain. (A) Representative images of TNFR1 and TNFR2 protein bands at approximately 55 kDa and 75 kDa, respectively, from Western blots. GAPDH: glyceraldehyde-3-phosphate dehydrogenase. (B) Densitometry analysis of the two TNFR proteins in the temporal cortex and cerebellum of the AD, HPC and ND brain. Data on the protein levels of TNFR1 and TNFR2 were normalized to GAPDH. Subsequently, the normalized data of AD and HPC groups were compared with ND group, and expressed as relative expression levels, where the data on ND were set as 100%. Values are expressed as the mean ± S.D. of the relative expression levels. n=10, *p<0.05 by Kruskal-Wallis non-parametric analysis with Steel-Dwass post-testing.