Amyloid β‐protein (Aβ)1–40 protects neurons from damage induced by Aβ1–42 in culture and in rat brain

Abstract

Previously, we found that amyloid b-protein (Ab)1-42 exhibits neurotoxicity, while Ab1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Ab1-40 against Ab1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Ab1-42 at concentrations higher than 2 lM, which was prevented by concurrent treatment with Ab1-40 in a dosedependent manner. However, metal chelators did not prevent Ab1-42-induced neuronal death. Circular dichroism spectroscopy showed that Ab1-40 inhibited the b-sheet transformation of Ab1-42. Thioflavin-T assay and electron microscopy analysis revealed that Ab1-40 inhibited the fibril formation of Ab1-42. In contrast, Ab1-16, Ab25-35, and Ab40-1 did not inhibit the fibril formation of Ab1-42 nor prevent Ab1-42-induced neuronal death. Ab1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Ab1-40. These results indicate that Ab1-40 protects neurons from Ab1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the b-sheet transformation and fibril formation of Ab1-42. Our data suggest a mechanism by which elevated Ab1-42/Ab1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.

Angiotensin-Converting Enzyme Converts Amyloid β-Protein 1–42 (Aβ1–42) to Aβ1–40, and Its Inhibition Enhances Brain Aβ Deposition

“…These results suggest that A␤ 1-40 is converted from nonfibril A␤ 1-42 within 8 h of incubation. We previously reported that A␤ 1-42 with random structures transformed to a ␤-sheet structure after 4 h of incubation at 37°C (Zou et al, 2003). Together with the present finding that the level of A␤ 1-40 converted from A␤ 1-42 increased until 8 h of incubation, it is possible that ACE generates A␤ 1-40 from A␤ 1-42 with both random and ␤-sheet structures.…”

“…Recently, we have shown that monomeric A␤ 1-40 has neuroprotective effects against metal-induced oxidative damage and A␤ 1-42 -induced neuronal death, whereas A␤ 1-42 is highly amyloidogenic and thus forms oligomers rapidly at very low concentrations, exerting strong neurotoxicity (Zou et al, 2002(Zou et al, , 2003. A␤ 1-40 , but not A␤ 1-42 , rescues neurons from ␤-or ␥-secretase inhibitor-induced cell death (Plant et al, 2003).…”

The Ratio of Monomeric to Aggregated Forms of Aβ40 and Aβ42 Is an Important Determinant of Amyloid-β Aggregation, Fibrillogenesis, and Toxicity

“…These studies have shown that A␤40 can inhibit the aggregation and fibril formation of A␤42 (38,41) and protect cultured neurons from A␤-induced neurotoxicity (40). In addition to confirming the findings of these studies, the present study serves as a critical contribution to the current understanding of A␤40 and A␤42 interactions by examining the specific interplay of biophysically defined A␤ species (and mixtures thereof).…”

“…A␤40 inhibits fibril formation by A␤42 (22,38), and co-incubation of the two A␤ variants leads to formation of mixed prefibrillar aggregates in vitro (39). A␤40 prevents A␤42-induced neurotoxicity in cultured cells and in vivo (40), underscoring the regulatory effects of A␤40/A␤42 ratio on important events associated with A␤ aggregation and toxicity. More recently, Yan and Wang (41) used differential NMR isotope labeling to demonstrate that A␤40 prevents aggregation of monomeric A␤42 and is capable of being exchanged for A␤42 monomer in A␤42 aggregates.…”

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

“…23). Previous studies have established the ratio of Aβ40 to Aβ42 as an important factor in determining the fibrillogenesis, toxicity and pathological distribution of Aβ in vivo [58][59][60] . The ability to obtain monomeric and protofibril preparations of Aβ42 and Aβ40 by SEC allowed us to characterize the interactions between these two peptides at the levels of monomers, protofibrils and fibrils.…”