Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

Abstract

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology.

Upregulation of Vitamin C Transporter Functional Expression in 5xFAD Mouse Intestine

“…These transgenic mice represent an accelerated AD model, developing AD pathologies by 2 months of age and reductions in synaptophysin, neuron loss and memory impairments that become evident by 5–6 months of age [ 16 ]. Twelve-month-old male 5xFAD mice and their wild-type (WT) littermate controls were maintained in standard housing conditions as described before [ 17 ] and provided ad libitum access to standard rodent chow (Envigo Teklad 2020x) and water. For AA supplementation studies, mice were provided 3.3g/l of AA in drinking water for 1 week and then used for oxidative stress response genes expression studies.…”

“…For AA supplementation studies, mice were provided 3.3g/l of AA in drinking water for 1 week and then used for oxidative stress response genes expression studies. Mice were anesthetized as described before [17] and the blood, hippocampus, and jejunum samples were collected for AA level determination, 14 C-AA uptake assay, molecular biological, and immunohistochemical analysis. Mice experimentation procedures were performed in accordance with the National Institutes of Health (NIH) rules and permitted by the University of California Irvine, Institutional Animal Care, and Use Committee (IACUC).…”

Mitigation of Alzheimer’s Disease Neuropathologies by Human Neural Stem Cell-derived Extracellular Vesicles

“…6C; P < 0.01 and P < 0.05, respectively for AD vs WT and AD + EV groups, respectively). It has been shown that the ratio of IgM to IgG is signi cantly decreased in human AD patients, and in the 5xFAD mouse model of AD [13]. A specialized subset of B1 cells produce IgM, the percentage of which was shown to be reduced in the AD mouse.…”

“…Microglia, the resident macrophages of the brain, become activated in an effort to engulf and clear the extracellular Aβ plaque deposits. However persistent microglial activation in AD eventually leads to a pro-in ammatory environment that includes increased expression of pro-in ammatory cytokines and reduced expression of anti-in ammatory cytokines [7,13,49]. Ultimately, this chronic in ammation creates a neurotoxic microenvironment that leads to loss of dendritic spines and neurons in the AD brain [49].…”

“…The increased neuroin ammation observed in AD is frequently associated with signi cant peripheral immune responses that correlate with adverse outcomes in human AD patients [13]. Therefore, the levels of in ammatory and anti-in ammatory cytokines in the plasma were evaluated.…”