Affected albumin endocytosis as a new neurotoxicity mechanism of amyloid beta.

Abstract

Senile plaques, a hallmark of Alzheimer's disease, are composed by Amyloid-Beta (Aβ). Aβ 25-35 toxicity is caused mainly by increasing reactive oxygen species (ROS), which is reversed by albumin preventing Aβ internalization. In addition, key cellular processes and basic cell functions require of endocytosis, particularly relevant in neurons. To understand the protective effect of albumin and the toxicity mechanism of Aβ, the need of albumin uptake for neurons protection as well as the possible influence of Aβ on albumin endocytosis were investigated. With this aim the influence of lectin from soybeans (LEC), which prevents albumin endocytosis, on the effects of Aβ 25-35 on cellular morphology and viability, ROS generation and Aβ uptake with and without albumin in neurons in primary culture was investigated. Influence of Aβ on albumin endocytosis was studied using FITC-labelled albumin. LEC did not modify Aβ effects with or without albumin on neuronal morphology, but increased cell viability. LEC increased ROS generation with and without Aβ in the same magnitude. Diminished Aβ internalization observed with albumin was not affected by LEC. In presence of Aβ albumin is internalized, but endosomes did not deliver their cargo to the lysosomes for degradation. It is concluded that formation of Aβ-albumin complex does not require of albumin internalization, thus is extracellular. Aβ affects albumin endocytosis preventing late endosomes and lysosomes degradation, probably caused by changes in albumin structure or deregulation in vesicular transport. Considering the consequences such as its osmotic effects, the inability to exert its antioxidant properties, its effects on neuronal plasticity and excitability albumin affected endocytosis induced by Aβ is proposed as a new physiopathology mechanism in AD. It is hypothesized that there is critical intraneuronal level above which albumin becomes toxic.