Amyloid β protein (AβP) forms senile plaques in the cerebrocortical blood vessels and brain parenchyma of patients with Alzheimer's disease (AD). The nonfamilial or sporadic AD (SAD), the most prevalent form of AD, has been correlated with an increased level of 40-residue AβP (AβP₁_-₄₀). However, very little is known about the role of AβP₁_-₄₀ in AD pathophysiology. We have examined the activity of AβP₁_-₄₀ reconstituted in phospholipid vesicles. A combined light fluorescence and atomic force microscope (AFM) was used to image the structure of reconstituted vesicles and ⁴⁵Ca²⁺ uptake was used as an assay for calcium permeability across the vesicular membrane. Vesicles reconstituted with fresh and globular AβP₁_-₄₀ contain a significant amount of AβP and exhibit strong immunofluorescence labeling with an antibody raised against the N-terminal domain of AβP, suggesting the incorporation of AβP₁_-₄₀ peptide in the vesicular membrane. Vesicles reconstituted with AβP₁_-₄₀ exhibited a significant level of ⁴⁵Ca²⁺ uptake. The vesicular calcium level saturated over time, showing an important ion channel characteristic. The ⁴⁵Ca²⁺ uptake was inhibited by (i) a monoclonal antibody raised against the N-terminal region of AβP and (ii) Zn²⁺. However, a reducing agent (DTT) did not inhibit the ⁴⁵Ca²⁺ uptake, indicating that the oxidation of AβP or its surrounding lipid molecules is not directly involved in AβP-mediated Ca²⁺ uptake. These findings provide biochemical and structural evidence that fresh and globular AβP₁_-₄₀ forms calcium-permeable channels and thus may induce cellular toxicity by regulating the calcium homeostasis in nonfamilial or sporadic Alzheimer's disease.

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