Beta-Amyloid and Oxidative Stress Jointly Induce Neuronal Death, Amyloid Deposits, Gliosis, and Memory Impairment in the Rat Brain

Abstract

Infusion of Fe²⁺, Aβ₄₂, and buthionine-sulfoximine (FAB), but not Aβ₄₂ alone or in combination with Fe²⁺, into the left cerebral ventricle of Long-Evans rats for 4 weeks induced memory impairment that was accompanied by increased hyperphosphorylated Tau protein levels in the CSF. FAB-infused animals displayed thioflavin-S-positive amyloid deposits, hyperphosphorylated Tau protein, neuronal loss, and gliosis. Animals treated with Aβ₄₂, Fe²⁺, or buthionine-sulfoximine alone or in combination failed to show the histological modifications seen with FAB. This data suggests that Aβ₄₂ is not sufficient to induce an Alzheimer’s disease-like symptomatology, and it supports a model whereby a decrease in the brain’s antioxidant defense system leads to the Aβ₄₂-independent oxidative stress necessary for the peptide to induce histopathological changes and memory loss.

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

“…Ab peptide is strongly implicated in the neurodegeneration underlying AD (Pike et al 1991;Whitson and Appel 1995). The mechanisms and pathways of oxidative stress triggered by Ab have also been shown in vivo and vitro (Butterfield and Boyd-Kimball 2004;Butterfield et al 2007Butterfield et al , 2010Lecanu et al 2006;Yatin et al 1999). Butterfield's group suggested that lipid peroxidation and protein oxidation may be related to Ab-induced oxidative stress in AD brain: (Butterfield and Boyd-Kimball 2004;Butterfield and Lauderback 2002).…”

“…Oxidative damage directly correlates with the presence of Ab deposits (Smith et al 1998) and Ab and oxidative stress jointly induce neuronal death, Ab deposits, gliosis, and memory impairment in AD (Lecanu et al 2006). Therefore, interventions of a vicious cycle of Ab generation and oxidation could have therapeutic application in AD and other neurodegenerative disorders.…”

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

“…The toxic mechanism of Aβ42-enriched oligomers supposedly causing AD remains highly debated, and several toxic modes of action have been suggested [82]: They may lead to impairment of long-term potentiation [83], permeabilization of cell membranes [84][85], oxidative stress [86], and calcium dyshomeostasis [87] [88]. Exposure of hydrophobic parts of the A variants is likely to cause aggregation and, in various contexts, interactions with membranes and other molecules in the cell to aggravate the toxicity of the peptides [85][89] [90].…”

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

“…These models involve a more complex process as it is still not possible to reproduce the disease by simply injecting AP. Other adjuvants are thus necessary as prooxidants or oxidation catalysts [4] . The intracerebral administration of AP can also provide useful information.…”