Structural Biology of Alzheimer's Disease
Universitat Autònoma de Barcelona (UAB)

Our research on the interaction of Alzheimer's amyloid peptides with biological membranes has resulted in the characterization of a type of 'off pathway' amorphous (non fibrillar) aggregates which form upon interaction with negatively charged membranes (PS membranes on the left figure: middle upper pannel). We have called theses aggregates Granullar Non-fibrillar Aggregates (GNAs). When interacting with neutral membranes (PC membranes on the left figure: left upper pannel) the amyloid peptides form the the typical fibrils.

Interestingly, the negative charges on the membranes may be due to lipid peroxidative processes and it turns out that the final cause for the formation of the GNAs is the decreased pH at the surface of the negatively charged membranes. GNAs can therefore form as well in the presence of neutral membranes if the pH of the bulk solution is around 5.5 (lefet figure: right upper pannel). Such a decrease in pH may be relevant in other fisiological conditions such as hypoxia following brain microbleedings.

The formation of fibrils and GNAs can be detected by transmission electron microscopy in the presence of neutral (left figure: left middle pannel)and negativley charged (left figure: right middle pannel) membranes respectively.

We have shown that compared to fibrils, GNAs are toxic in cell culture.

GNAs may represent a molecular link between amyloid peptides and other important factors in the development of the pathology: on the one hand oxidative stress (via lipid peroxidation) and on the other vascular disorders (microbleedings) related to hypoxia and local acidification (see schemes in the left figure, lower pannel, and the right figure).GNAs may be a new farmacological target.