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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: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).

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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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