Beta-Amyloid Peptides Enhance the Proliferative Response of Activated CD4+CD28+ Lymphocytes from Alzheimer Disease Patients and from Healthy Elderly

Alzheimer's disease (AD) is the most frequent form of dementia among elderly. Despite the vast amount of literature on non-specific immune mechanisms in AD there is still little information about the potential antigen-specific immune response in this pathology. It is known that early stages of AD include β-amyloid (Aβ)- reactive antibodies production and inflammatory response. Despite some evidence gathered proving cellular immune response background in AD pathology, the specific reactions of CD4+ and CD8+ cells remain unknown as the previous investigations yielded conflicting results. Here we investigated the CD4+CD28+ population of human peripheral blood T cells and showed that soluble β-amyloids alone were unable to stimulate these cells to proliferate significantly, resulting only in minor, probably antigen-specific, proliferative response. On the other hand, the exposure of in vitro pre-stimulated lymphocytes to soluble Aβ peptides significantly enhanced the proliferative response of these cells which had also lead to increased levels of TNF, IL-10 and IL-6. We also proved that Aβ peptide-enhanced proliferative response of CD4+CD28+ cells is autonomous and independent from disease status while being associated with the initial, ex vivo activation status of the CD4+ cells. In conclusion, we suggest that the effect of Aβ peptides on the immune system of AD patients does not depend on the specific reactivity to Aβ epitope(s), but is rather a consequence of an unspecific modulation of the cell cycle dynamics and cytokine production by T cells, occurring simultaneously in a huge proportion of Aβ peptide-exposed T lymphocytes and affecting the immune system performance

Healthy and AD individuals can be clustered according to high or low level of response to modulatory action of β-amyloids.

<p>Comparison of proliferative dynamic parameters of CD4⁺CD28⁺ cells from individuals clustered according to high (high responders) and low response to Aβ 1–42 (low responders) Cluster analysis for combined groups of AD patients and healthy elderly according to enhancement of proliferative response of CD4⁺CD28⁺ cells to anti-CD3+Aβ 1–42 stimulation was performed as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033276#s2" target="_blank">Materials and Methods</a>. Highly significant differences between “high” and “low” responders can be observed regarding the numbers of divisions per cell (A), cell cycle length (B) and the percentages of dividing cells (C).Relevant p values are shown. Not significant differences are marked n.s.</p

Major features of high responders and their CD4⁺ lymphocytes as compared to low responders.

<p>Value observed for high responders is shown as significantly higher (↑,↑↑) or lower (↓) than observed for low responders.</p><p>N.S. – lack of statistically significant difference between high and low responders.</p

Proposed model explaining the difference in reactivity to Aβ during <i>in vivo</i> and <i>in vitro</i> stimulation between the CD4⁺CD28⁺ lymphocytes of high (HR) and low responders (LR).

<p>Arrows connect the type of responder (high vs. low) with expected response to stimulation. Dotted arrows: environmental Ag stimulation and response; dashed arrows: Aβ-specific (antigenic) stimulation and response; solid arrows: Aβ - immunomodulatory response.</p

Activation status of the CD4⁺ lymphocytes of individuals exhibiting high or low response to Aβ is different.

<p>Percentages of CD4⁺ cells bearing activation markers: CD4⁺CD69⁺ (A) and CD4⁺HLA-DR⁺ (B) ex vivo are significantly elevated in the group of high responders (high) in comparison with low responders (low). No differences exist concerning CD4⁺CD25⁺ percentage between two investigated groups (C). Data are presented as medians, 25^th and 75^th percentiles and minimal/maximal values. Statistically significant differences are marked with * (P = <0,05).</p

Dementia, infections and vaccines: 30 years of controversy

This paper reports the proceedings of a virtual meeting convened by the European Interdisciplinary Council on Ageing (EICA), to discuss the involvement of infectious disorders in the pathogenesis of dementia and neurological disorders leading to dementia. We recap how our view of the infectious etiology of dementia has changed over the last 30&nbsp;years in light of emerging evidence, and&nbsp;we present evidence in support of the implication of infection in dementia, notably Alzheimer's disease (AD). The bacteria and viruses thought to be responsible for neuroinflammation and neurological damage are reviewed. We then review the genetic basis for neuroinflammation and dementia, highlighting the genes that are currently the focus of investigation as potential targets for therapy. Next, we describe the antimicrobial hypothesis of dementia, notably the intriguing possibility that amyloid beta may itself possess antimicrobial properties. We further describe the clinical relevance of the gut-brain axis in dementia, the mechanisms by which infection can move from the intestine to the brain, and recent findings regarding dysbiosis patterns in patients with AD. We review the involvement of specific pathogens in neurological disorders, i.e. SARS-CoV-2, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1), and influenza. Finally, we look at the role of vaccination to prevent dementia. In conclusion, there is a large body of evidence supporting the involvement of various infectious pathogens in the pathogenesis of dementia, but large-scale studies with long-term follow-up are needed to elucidate the role that infection may play, especially before subclinical or clinical disease is present