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AB42 and polyamines: Elucidating a potential mechanism of amyloid‐mediated apoptosis and aggregation
Author(s) -
Sandberg Alexandra A.,
Johnson Austin,
Fudge Dylan,
Melgar Stephanie,
Hicks Carrie,
Patterson David,
Vacano Guido,
Margittai Martin,
Weismiller Hilary,
Harvey Sebastian,
Hernandez Luis,
Caviedes Pablo,
Ledreux Aurélie,
Qin Yan,
Granholm AnnCharlotte,
Linseman Daniel,
Paredes Daniel
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039915
Subject(s) - ornithine decarboxylase , hippocampal formation , apoptosis , pathogenesis , biology , microbiology and biotechnology , programmed cell death , transfection , alzheimer's disease , chemistry , biochemistry , enzyme , medicine , endocrinology , immunology , disease , gene
Background The dysfunctional accumulation of amyloid beta (Aβ) plaques in neuronal cells is widely regarded as a hallmark sign of Alzheimer’s disease (AD). However, the mechanisms by which Aβ causes the rampant apoptosis that leads to the characteristic memory loss and dementia observed in AD patients are much less understood. In this study, we investigated the regulatory relationship between Aβ 42 , a particularly toxic member of the Aβ peptide family, and polyamines (PA), a ubiquitous class of molecules associated with cell growth, proliferation, and immune response. Increasing evidence has suggested that the PA pathway is changed in AD. For example, increased levels of enzymes in the PA synthesis pathway and altered PA metabolomics have been found in the AD brain. Here, we sought to investigate the relationship between PA synthesis and disease pathogenesis, specifically Aβ aggregation and in turn, neuronal death. Method HT22 hippocampal cells were transiently transfected with bicistronic plasmids allowing for expression of DsRed alone or co‐expression with Aβ 42. We then examined the effects of Aβ 42 on expression of the rate limiting enzyme for PA synthesis, ornithine decarboxylase (ODC) and in turn, PA levels. Irreversible ODC inhibitor, L‐difluoromethylornithine (DFMO) was used to examine effects on Aβ 42 aggregation and neuronal apoptosis. Hippocampal tissue from human sporadic AD and age matched controls were also assessed for PA concentration and ODC expression. Results We found that Aβ 42 increased PA levels in a dose‐dependent fashion through enhanced expression of ODC in HT22 hippocampal cells. Treatment with DFMO significantly reduced this increase in PA as well as aggregation of Aβ 42 and Aβ 42 ‐induced apoptosis. Lastly, levels of spermidine and spermine as well as ODC expression were significantly increased in sporadic AD human hippocampal tissue in comparison to age‐matched controls. Conclusion These data suggest that increased intracellular concentrations of PA are not only a response to Aβ 42, but they also promote Aβ 42 toxicity by enhancing aggregation. Secondarily, DFMO may be a novel therapeutic to mitigate Aβ 42 toxicity and reduce amyloid plaque load in patients with AD.