The Production of Amyloid β Peptide Is a Critical Requirement for the Viability of Central Neurons

Abstract

The amyloid beta peptide (Abeta) is a product of the sequential gamma- and beta-secretase cleavage of amyloid precursor protein. Inhibitors of secretase enzymes have been proposed as a potential therapeutic strategy in the treatment of Alzheimer's disease. Here, we investigate the effect of inhibiting these key enzymes on the viability of a range of cell types. Treatment of rat cortical neurons for 24 hr with secretase inhibitors or an antibody that binds Abeta resulted in a marked reduction in cell viability, as measured by MTT reduction. Incubation with secretase inhibitors caused similar effects on other neuronal cell types (rat cerebellar granule neurons and the human SH-SY5Y cell line). Interestingly, rat astrocytes and a number of non-neuronal cell lines investigated (HEK293, DDT1-FM2, and human teratorhabdoid tumor cells) were unaffected by incubation with secretase inhibitors. The coincubation of Abeta1-40 prevented the toxicity of secretase inhibitors in neuronal cells. Abeta1-40 was protective in a concentration-dependent manner, and its effects were significant at concentrations as low at 10 pm. Importantly, the protective effects of Abeta were Abeta size-form specific, with the Abeta1-42 size form affording limited protection and the Abeta25-35 size form having very little protective effect. The present study demonstrates that inhibition of beta-or gamma-secretase activity induces death in neuronal cells. Importantly, this toxicity, which our data suggest is a consequence of a decline in neuronal Abeta levels, was absent in non-neuronal cells. This study further supports a key physiological role for the enigmatic Abeta peptide.

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

“…Aβ depletion is lethal to cultured neurons (Plant et al ., 2003), and its blockade impairs learning and memory in adult mice (Morley et al ., 2010; Puzzo et al ., 2011, 2017). Low doses of synthetic Aβ ensemble mimic the memory enhancement effects of endogenous Aβ (Puzzo et al ., 2008), likely via the regulation of transmitter release (Morley et al ., 2010; Puzzo et al ., 2011).…”

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

“…For example, Aβ1‐40 prevents degradation of cell membrane lipids by inhibiting auto‐oxidation of CSF and plasma lipoproteins (Kontush et al., 2001), an event known to be increased in AD patients (Bassett et al., 1999). The Aβ1‐40 peptide is further the most effective Aβ specie to rescue cultured neurons which are dying in response to endogenous Aβ inhibition (Plant, Boyle, Smith, Peers & Pearson, 2003). Our own cell viability results, showing decreased cell death as well as decreased caspase 3/7 activity after monomer Aβ1‐40 exposure, support the idea that Aβ1‐40 is beneficial for cell survival.…”

Photoluminescence intensity ratio of Eu‐conjugated lactates—A simple optical imaging technique for biomarker analysis for critical diseases

“…7 F 2 ) transition. This indicates that Eu 3+ ion is located at high symmetry sites [35], whereas Figure 7B shows luminescence spectra of the same concentrations of lactic acid in serum and 1 mM Eu(NO 3 ) 3 .6H 2 O aqueous solution. This figure shows small change in luminescence intensities at 591 and 616 nm as compared to Figures 5 and 7A.…”

“…Many studies have shown that Eu 3+ luminescence peak at 5 D 0 ! 7 F 1 transition is relatively strong, and exhibited no/little change on the surrounding ligand environment due to its MD contribution [35][36][37][38][39][40]. Similarly, the 5 D 0 !…”

“…Similarly, the 5 D 0 ! 7 F 2 electronic transition is predominantly electric dipole and the intensity is highly sensitive to the Eu 3+ coordinate environment [31,[33][34][35] as mentioned above.…”