Anti-Aβ single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer’s disease

Martín-Peña, Alfonso; Rincón-Limas, Diego E.; Fernández-Fúnez, Pedro

doi:10.1038/s41598-017-11594-2

Cited by 13 publications

(11 citation statements)

References 52 publications

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“…2 ). At 27 °C, however, the volume of the MB lobes (axonal) and, more prominently, the calyxes of the Kenyon Cells (somatic and dendritic) tended to shrink due to Aβ42-induced neurodegeneration; but this effect does not became significant until day 20 post-eclosion, as it was previously reported 25 . Remarkably, the memory impairments were present (i.e.…”

Section: Resultssupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

“…We had previously developed a Drosophila model of AD 25 , in which we specifically expressed the Aβ 42 construct 26 in the mushroom body (MB) neurons and monitored memory acquisition throughout aging, and up to 30 days of age. Our fly model displayed severe memory impairments after olfactory classical conditioning 25 . As memory was drastically impaired since day 1 post-eclosion, we decided to lower the expression level of the Aβ 42 construct 26 and monitor the progression of these memory deficits under these new conditions.…”

Section: Resultsmentioning

confidence: 99%

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Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease

Martín-Peña

Rincón-Limas

Fernández-Fúnez

2018

Sci Rep

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Proteinopathies constitute a group of diseases in which certain proteins are abnormally folded leading to aggregation and eventual cell failure. Most neurodegenerative diseases belong to protein misfolding disorders and, among them, Alzheimer’s disease (AD) is the most prevalent. AD is characterized by accumulation of the amyloid-β42 (Aβ42) peptide in the extracellular space. Hence, we genetically engineered a molecular chaperone that was selectively delivered to this cellular location. It has been reported that the heat shock protein 70 (Hsp70) binds Aβ42 preventing self-aggregation. Here, we employed two isoforms of the Hsp70, cytosolic and extracellular, to evaluate their potential protective effect against the memory decline triggered by extracellular deposition of Aβ42. Both Hsp70 isoforms significantly improved memory performance of flies expressing Aβ42, irrespective of their age or the level of Aβ42 load. Using olfactory classical conditioning, we established a Drosophila model of AD based on Aβ42 neurotoxicity and monitored memory decline through aging. The onset of the memory impairment observed was proportional to the cumulative level of Aβ42 in the Drosophila brain. These data support the use of this Drosophila model of AD to further investigate molecules with a protective activity against Aβ42-induced memory loss, contributing to the development of palliative therapies for AD.

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Section: Resultssupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease

Martín-Peña

Rincón-Limas

Fernández-Fúnez

2018

Sci Rep

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“…These have been used as the basis for genetic and/or pharmacological screening [ 114 – 117 ]. Other novel approaches to ameliorating AD symptoms in Drosophila models include immunotherapy and photodynamics [ 118 , 119 ]. In addition, the contribution of nonneuronal cell types to AD disease progression is well established.…”

Section: Advantages Of Using Drosophila To Modementioning

confidence: 99%

UsingDrosophilaModels of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer’s Disease

O’Keefe

Denton

2018

BioMed Research International

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Autophagy is a conserved catabolic pathway that involves the engulfment of cytoplasmic components such as large protein aggregates and organelles that are delivered to the lysosome for degradation. This process is important in maintaining neuronal function and raises the possibility of a role for autophagy in neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent form of these diseases and is characterized by the accumulation of amyloid plaques in the brain which arise due to the misfolding and aggregation of toxic peptides, including amyloid beta (Aβ). There is substantial evidence from both AD patients and animal models that autophagy is dysregulated in this disease. However, it remains to be determined whether this is protective or pathogenic as there is evidence that autophagy can act to promote the degradation as well as function in the generation of toxic Aβ peptides. Understanding the molecular details of the extensive crosstalk that occurs between the autophagic and endolysosomal cellular pathways is essential for identifying the molecular details of amyloid toxicity. Drosophila models that express the toxic proteins that aggregate in AD have been generated and have been shown to recapitulate hallmarks of the disease. Here we focus on what is known about the role of autophagy in amyloid toxicity in AD from mammalian models and how Drosophila models can be used to further investigate AD pathogenesis.

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“…These events include decreased presynaptic connections, altered mitochondrial localization and reduced postsynaptic protein levels (Mhatre et al, 2014). Other models are based on the expression of human β -amyloid peptides including: Aβ40 (Iijima et al, 2004), which does not produce plaque formation but causes age-dependent learning defects; Aβ42 that elicits synaptic alterations and locomotor, survival and learning impairments (Iijima et al, 2008;Martin-Peña et al, 2017;Martín-Peña et al, 2018), and other Aβ aggregation-prone models containing human AD mutations like Aβ42-Arc (Crowther et al, 2005;Iijima et al, 2008). In addition, the 2X-UAS-Aβ42 construct, consisting in two tandem copies of the human Aβ42 fused to a secretion signal, yields stronger neurotoxic phenotypes than other single-copy models.…”

Section: Introductionmentioning

confidence: 99%

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

Arnés

Romero

Casas‐Tintó

et al. 2019

Preprint

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Alzheimer's disease is, to a large extent, a disease of the synapse triggered by the unbalanced amyloidogenic cleavage of the amyloid precursor protein APP. Excess of Aβ42 peptide in particular is considered a hallmark of the disease. Here we drive the expression of the human Aβ42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. We show that the neuronal expression of the human peptide elicits progressive toxicity in the adult. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as life-span reduction. The Aβ42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes: bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the co-expression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and Thioflavin-positive amyloid deposits. Mechanistically, we suggest that Aβ42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Finally, along with these in vivo experiments we further analyze Aβ42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where Aβ42 aggregation into large insoluble deposits is reproduced. Taken together, these results uncover a potential novel pharmacological strategy against this disease with PI3K activation as a target.

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Anti-Aβ single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer’s disease

Cited by 13 publications

References 52 publications

Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease

Engineered Hsp70 chaperones prevent Aβ42-induced memory impairments in a Drosophila model of Alzheimer’s disease

UsingDrosophilaModels of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer’s Disease

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

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