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IgM response against amyloid-beta in aging: a potential peripheral protective mechanism.

ABSTRACT: BACKGROUND:The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (A?) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of A?. METHODS:We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to A? peptide 1-42, A? fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD. RESULTS:Our studies revealed that DCs from healthy aged subjects display weak reactivity towards the A? peptide and no reactivity towards A? fibrils and tau compared with their young counterparts. An analysis of old and young PBMCs revealed that there is no significant T-cell memory against A? peptide, fibrils, or tau. Remarkably, the plasma levels of IgM antibodies specific to A? peptide 1-42 were significantly increased in aged subjects compared with young subjects, while IgG levels were comparable. A? peptide-specific IgM and IgG levels were also determined in the plasma of AD subjects compared with age-matched controls to demonstrate that the immune response against A? is stronger in AD patients. A decline in A? peptide-specific IgM antibodies was observed in AD patients compared with age-matched controls. In contrast, the levels of IgG as well as interleukin-21, the major cytokine involved in class switching, were increased in AD and patients with mild cognitive impairment, indicating a strong immune response against A?. CONCLUSIONS:Collectively, low immunogenicity of A? in healthy controls may prevent inflammation while the generation of specific IgM antibodies may help in the clearance of A? in healthy subjects.

SUBMITTER: Agrawal S

PROVIDER: S-EPMC6097437 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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IgM response against amyloid-beta in aging: a potential peripheral protective mechanism.

Agrawal Sudhanshu S Abud Edsel M EM Snigdha Shikha S Agrawal Anshu A

Alzheimer's research & therapy 20180816 1

<h4>Background</h4>The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (Aβ) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of Aβ.<h4>Methods</h4>We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjec ...[more]

PMID: 30115117

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Project description:Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-? (A?) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive A? production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV) would react differentially from the 2 DIV cells upon treatment with 1000 nM A?1-42 for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after A? treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2) and milk fat globule-EGF factor 8 protein (MFG-E8) levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1) and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2), TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1) cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9) was marked in 16 DIV cells. Increased senescence-associated ?-galactosidase (SA-?-gal) and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by A? in 2 DIV microglia. Additionally, A? downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while increased the number of CD86+ cells in 16 DIV microglia. Simultaneous M1 and M2 markers were found after A? treatment, but at lower expression in the in vitro aged microglia. Data show key-aging associated responses by microglia when incubated with A?, with a loss of reactivity from the 2 DIV to the 16 DIV cells, which course with a reduced phagocytosis, migration and lower expression of inflammatory miRNAs. These findings help to improve our understanding on the heterogeneous responses that microglia can have along the progression of AD disease and imply that therapeutic approaches may differ from early to late stages.

Project description:BackgroundTherapeutic intervention of numerous brain-associated disorders currently remains unrealized due to serious limitations imposed by the blood-brain-barrier (BBB). The BBB generally allows transport of small molecules, typically <600 daltons with high octanol/water partition coefficients, but denies passage to most larger molecules. However, some receptors present on the BBB allow passage of cognate proteins to the brain. Utilizing such receptor-ligand systems, several investigators have developed methods for delivering proteins to the brain, a critical requirement of which involves covalent linking of the target protein to a carrier entity. Such covalent modifications involve extensive preparative and post-preparative chemistry that poses daunting limitations in the context of delivery to any organ. Here, we report creation of a 36-amino acid peptide transporter, which can transport a protein to the brain after routine intravenous injection of the transporter-protein mixture. No covalent linkage of the protein with the transporter is necessary.ApproachA peptide transporter comprising sixteen lysine residues and 20 amino acids corresponding to the LDLR-binding domain of apolipoprotein E (ApoE) was synthesized. Transport of beta-galactosidase, IgG, IgM, and antibodies against amyloid plques to the brain upon iv injection of the protein-transporter mixture was evaluated through staining for enzyme activity or micro single photon emission tomography (micro-SPECT) or immunostaining. Effect of the transporter on the integrity of the BBB was also investigated.Principal findingsThe transporter enabled delivery to the mouse brain of functional beta-galactosidase, human IgG and IgM, and two antibodies that labeled brain-associated amyloid beta plaques in a mouse model of Alzheimer's disease.SignificanceThe results suggest the transporter is able to transport most or all proteins to the brain without the need for chemically linking the transporter to a protein. Thus, the approach offers an avenue for rapid clinical evaluation of numerous candidate drugs against neurological diseases including cancer. (299 words).

Project description:The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy-enhancers-treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, and mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy-enhancers-treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aβ-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with ad.

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IgM response against amyloid-beta in aging: a potential peripheral protective mechanism.

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IgM response against amyloid-beta in aging: a potential peripheral protective mechanism.

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