Neurotoxicity of Human Amylin in Rat Primary Hippocampal Cultures: Similarity to Alzheimer's Disease Amyloid‐β Neurotoxicity

Abstract

Amylin, a 37-amino-acid amyloidogenic peptide, bears biophysical similarities to the amyloid-beta peptide (A beta) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar to that previously observed with A beta(1-40). Treatment with human amylin(1-37) resulted in prominent toxicity as assessed by phase-contrast microscopy and quantification of lactate dehydrogenase in the medium. Amylin-induced neurotoxicity was morphologically similar to that induced by A beta(1-40). In contrast, the nonamyloidogenic rat amylin showed negligible neurotoxicity despite having 95% sequence similarity to human amylin. Only full-length human amylin was toxic; various amylin peptide fragments including amino acid residues 20-29 were nontoxic at similar concentrations. These studies suggest that unrelated amyloidogenic peptides like human amylin and A beta can adopt a similar neurotoxic conformation in vitro. Similar conformation-dependent neurotoxicity may drive the prominent neurite degeneration around compacted but not diffuse deposits of A beta in Alzheimer's disease.

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

“…This is consistent with an earlier paper suggesting that full-length human amylin resulted in prominent toxicity in rat primary HN cells [24]. Also, it has been shown that, in contrast to full-length amylin, which promotes self-assembly and aggregation, various amylin peptide fragments (including amino acid residues 20-29) were non-toxic at similar concentrations in rat primary hippocampal cultures, suggesting that secondary structure may play a predominant role in human amylin neurotoxicity [24]. Hence, further work needs to be done using various amylin peptide fragments not only in hippocampal cells but also in hypothalamic cells.…”

“…It has also been proposed that high levels of leptin are associated with lower rates of dementia and Alzheimer's disease [31]. Amylin acts at the level of the CNS to produce anorectic effects, alter physiological responses to feeding (and possibly thirst and drinking behaviour) [23] and drive the neurite degeneration in Alzheimer's disease [24]. Adiponectin has been proposed to exert multiple regulatory functions primarily through action on the CNS [26].…”

“…It belongs to the limbic system and plays an important part in the processing of information from short-term memory to long-term memory and spatial navigation [10][11][12]. In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among initial symptoms [24,31]. It has been shown that leptin facilitates spatial learning and memory [14][15][16] and that it produces antidepressant-like effects [17][18][19][20][21][22].…”

“…Amylin has a beneficial effect on the CNS to alter physiological responses to feeding [23]. It has been demonstrated that amylin induces neurotoxicity in embryonic rat hippocampal primary cultures in vitro and this may drive the prominent neurite degeneration in Alzheimer's disease [24]. By contrast, central administration of amylin resulted in impaired memory retention in mice given strong training but had no effect on the retention of mice given weak training [25], suggesting that the mechanisms of action by which amylin alters memory processing in the hippocampus are different for peripheral and central administration.…”

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

“…Other amyloidogenic proteins, which do not share sequence homology with A␤ (e.g.. prion and amylin), do form structurally similar extracellular deposits and have been found to have similar neurotoxic activity in vitro (47,48). One possible mechanism that could explain the common biological activity seen with different amyloidogenic peptides is ␤-sheet augmentation, whereby a peptide forms a "peptide-surface association" (49) either by inserting itself into a ␤-sheet-containing domain (50), which has been proposed for other diseases involving protein conformational changes (51)(52)(53)(54), or by adding to the edge of an anti-parallel ␤-strand, as has been implicated in regulating protein associations governing signal transduction pathways and assembly interactions in certain viral capsids (49).…”