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The aqueous phase of Alzheimer's disease brain contains assemblies built from ?4 and ?7 kDa A? species.

ABSTRACT: INTRODUCTION:Much knowledge about amyloid ? (A?) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble A? in human brain. METHODS:We analyzed aqueous extracts from multiple AD brains using an array of techniques. RESULTS:Brains can contain at least four different A? assembly forms including: (i) monomers, (ii) a ?7 kDa A? species, and larger species (iii) from ?30-150 kDa, and (iv) >160 kDa. High molecular weight species are by far the most prevalent and appear to be built from ?7 kDa A? species. The ?7 kDa A? species resist denaturation by chaotropic agents and have a higher A?42/A?40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1. DISCUSSION:Further analysis of brain-derived ?7 kDa A? species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities.

SUBMITTER: Mc Donald JM

PROVIDER: S-EPMC4592782 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species.

Mc Donald Jessica M JM O'Malley Tiernan T TT Liu Wen W Mably Alexandra J AJ Brinkmalm Gunnar G Portelius Erik E Wittbold William M WM Frosch Matthew P MP Walsh Dominic M DM

Alzheimer's & dementia : the journal of the Alzheimer's Association 20150404 11

<h4>Introduction</h4>Much knowledge about amyloid β (Aβ) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Aβ in human brain.<h4>Methods</h4>We analyzed aqueous extracts from multiple AD brains using an array of techniques.<h4>Results</h4>Brains can contain at least four different Aβ assembly forms including: (i) monomers, (ii) a ∼7 kDa Aβ species, and larger species (iii) from ∼30-150 kDa, and (iv) >160 kDa. High molecular ...[more]

PMID: 25846299

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Project description:Background: A fundamental question in Alzheimer's disease (AD) is whether amyloid-β (Aβ) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Aβ, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E ε4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, in vitro and cerebrospinal fluid (CSF) only, indicated one possible native function of Aβ peptides is the allosteric modulation of acetylcholine homeostasis, via molecular interactions between Aβ, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAβACs). Methods: Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Aβ, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples. Results: We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Aβ peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Aβ was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of APOE genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Aβ forms were closely matched between CSF and brain samples. This evinces that the detected Aβ-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain. Conclusions: In conclusion, both light homomeric Aβ oligomers and heteromeric Aβ-ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and APOE4 genotype. Deeper knowledge of the physiological function of Aβ is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.

Project description:Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid β-protein (Aβ). Aβ42 forms are especially neurotoxic and highly associated with Alzheimer's disease (AD). As a ligand of CSF1R, IL-34 may be relevant to innate immune responses in AD. To investigate how IL-34 affects macrophage phenotype in response to structurally defined and stabilized Aβ42 oligomers and preformed fibrils, we characterized murine BMMO cultured in media containing M-CSF, IL-34, or regimens involving both cytokines. We found that the immunological profile and activation phenotype of IL-34-stimulated BMMO differed significantly from those cultured with M-CSF alone. Specifically, macrophage uptake of fibrillar or oligomeric Aβ42 was markedly reduced following exposure to IL-34 compared to M-CSF. Surface expression of type B scavenger receptor CD36, known to facilitate Aβ recognition and uptake, was modified following treatment with IL-34. Similarly, IL-34 macrophages expressed lower levels of proteins involved in both Aβ uptake (triggering receptor expressed on myeloid cells 2, TREM2) as well as Aβ-degradation (matrix metallopeptidase 9, MMP-9). Interestingly, intracellular compartmentalization of Aβ visualized by staining of early endosome antigen 1 (EEA1) was not affected by IL-34. Macrophage characteristics associated with an anti-inflammatory and pro-wound healing phenotype, including processes length and morphology, were also quantified, and macrophages stimulated with IL-34 alone displayed less process elongation in response to Aβ42 compared to those cultured with M-CSF. Further, monocytes treated with IL-34 alone yielded fewer mature macrophages than those treated with M-CSF alone or in combination with IL-34. Our data indicate that IL-34 impairs monocyte differentiation into macrophages and reduces their ability to uptake pathological forms of Aβ. Given the critical role of macrophage-mediated Aβ clearance in both murine models and patients with AD, future work should investigate the therapeutic potential of modulating IL-34 in vivo to increase macrophage-mediated Aβ clearance and prevent disease development.

Dataset Information

The aqueous phase of Alzheimer's disease brain contains assemblies built from ?4 and ?7 kDa A? species.

Publications

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species.

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