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The A? protofibril selective antibody mAb158 prevents accumulation of A? in astrocytes and rescues neurons from A?-induced cell death.

ABSTRACT: Currently, several amyloid beta (A?) antibodies, including the protofibril selective antibody BAN2401, are in clinical trials. The murine version of BAN2401, mAb158, has previously been shown to lower the levels of pathogenic A? and prevent A? deposition in animal models of Alzheimer's disease (AD). However, the cellular mechanisms of the antibody's action remain unknown. We have recently shown that astrocytes effectively engulf A?42 protofibrils, but store rather than degrade the ingested A? aggregates. In a co-culture set-up, the incomplete degradation of A?42 protofibrils by astrocytes results in increased neuronal cell death, due to the release of extracellular vesicles, containing N-truncated, neurotoxic A?.The aim of the present study was to investigate if the accumulation of A? in astrocytes can be affected by the A? protofibril selective antibody mAb158. Co-cultures of astrocytes, neurons, and oligodendrocytes, derived from embryonic mouse cortex, were exposed to A?42 protofibrils in the presence or absence of mAb158.Our results demonstrate that the presence of mAb158 almost abolished A? accumulation in astrocytes. Consequently, mAb158 treatment rescued neurons from A?-induced cell death.Based on these findings, we conclude that astrocytes may play a central mechanistic role in anti-A? immunotherapy.

SUBMITTER: Sollvander S

PROVIDER: S-EPMC5875007 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.

Söllvander Sofia S Nikitidou Elisabeth E Gallasch Linn L Zyśk Marlena M Söderberg Linda L Sehlin Dag D Lannfelt Lars L Erlandsson Anna A

Journal of neuroinflammation 20180328 1

<h4>Background</h4>Currently, several amyloid beta (Aβ) antibodies, including the protofibril selective antibody BAN2401, are in clinical trials. The murine version of BAN2401, mAb158, has previously been shown to lower the levels of pathogenic Aβ and prevent Aβ deposition in animal models of Alzheimer's disease (AD). However, the cellular mechanisms of the antibody's action remain unknown. We have recently shown that astrocytes effectively engulf Aβ<sub>42</sub> protofibrils, but store rather t ...[more]

PMID: 29592816

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Project description:Adenosine monophosphate (AMP)?activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen. While neuroprotective approaches by definition focus on neurons, that are more sensitive under cell stress conditions, astrocytes play an important role in the cerebral energy homeostasis during ischemia. Therefore, the protection of astrocytic cells or other glial cells may contribute to the preservation of neuronal integrity and function. In the present study, it was thus hypothesized that a preventive induction of energy deprivation?activated signaling pathways via AMPK may protect astrocytes from hypoxia and glucose deprivation. Hypoxia?induced cell death was measured in a paradigm of hypoxia and partial glucose deprivation in vitro in the immortalized human astrocytic cell line SVG. Both the glycolysis inhibitor 2?deoxy?d?glucose (2DG) and the AMPK activator A?769662 induced the phosphorylation of AMPK, resulting in mTORC1 inhibition, as evidenced by a decrease in the phosphorylation of the target ribosomal protein S6 (RPS6). Treatment with both 2DG and A?769662 also decreased glucose consumption and lactate production. Furthermore, A?769662, but not 2DG induced an increase in oxygen consumption, possibly indicating a more efficient glucose utilization through oxidative phosphorylation. Hypoxia?induced cell death was profoundly reduced by treatment with 2DG or A?769662. On the whole, the findings of the present study demonstrate, that AMPK activation via 2DG or A?769662 protects astrocytes under hypoxic and glucose?depleted conditions.

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene. A second copy, SMN2, is similar to SMN1 but produces ∼10% SMN protein because of a single-point mutation that causes splicing defects. Chronic low levels of SMN cause accumulation of co-transcriptional R-loops and DNA damage leading to genomic instability and neurodegeneration in SMA. Severity of SMA disease correlates inversely with SMN levels. SMN2 is a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SMN genes are largely unknown. We report that zinc finger protein ZPR1 binds to RNA polymerase II, interacts in vivo with SMN locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and influences SMN2 expression levels in SMA patient cells. ZPR1 overexpression in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice. ZPR1-dependent rescue improves growth and motor function and increases the lifespan of male and female SMA mice. ZPR1 reduces neurodegeneration in SMA mice and prevents degeneration of cultured primary spinal cord neurons derived from SMA mice. Further, we show that the low levels of ZPR1 associated with SMA pathogenesis cause accumulation of co-transcriptional RNA-DNA hybrids (R-loops) and DNA damage leading to genomic instability in SMA mice and patient cells. Complementation with ZPR1 elevates senataxin levels, reduces R-loop accumulation and rescues DNA damage in SMA mice, motor neurons and patient cells. In conclusion, ZPR1 is critical for preventing accumulation of co-transcriptional R-loops and DNA damage to avert genomic instability and neurodegeneration in SMA. ZPR1 enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPR1 represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA.

Dataset Information

The A? protofibril selective antibody mAb158 prevents accumulation of A? in astrocytes and rescues neurons from A?-induced cell death.

Publications

The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.

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