Amyloid Formation in Alzheimer Disease

Alzheimer disease (AD), the most common form of dementia in adults, appears sporadically and in an autosomal dominant form. Presently, treatment for AD is unavailable. A hallmark characteristic of AD is the deposition of amyloid as insoluble fibrous masses in extracellular senile plaques. AmyloidÕs main component is a 4.3-kDa amyloid-b peptide (Ab), which also exists in a soluble form (sAb) normally circulating in human cerebrospinal fluid and plasma. Since the discovery of sAb, a fundamental question in AD is how the same amino acid sequence can exist in a soluble and in a fibrillar form. Synthetic peptides containing the Ab sequence form amyloid-like fibrils in vitro exhibiting morphological, structural, and tinctorial properties identical to the amyloid fibrils extracted from the AD senile plaques. By using synthetic Ab analogues, we showed that the conformation of the Ab N-terminal fragment modulates amyloid formation, rendering two different conformational species of Ab in solution: One is highly amyloidogenic, toxic for neurons, partially resistant to proteolysis, and containing a high level of b-sheet secondary structure; the other is slowly amyloidogenic, sensitive to proteolytic degradation, poorly neurotoxic, and adopts mainly an a-helical or random coil conformation. We propose that sAb corresponds to the nonamyloidogenic Ab conformer and that the transition rendering the pathological amyloidogenic structure from its physiological conformation can be an important step in the fibrillogenesis process. This transition is spontaneously slow in vitro and enhanced by apolipoprotein E, a protein genetically associated to AD.

Based on the knowledge of the structural determinants for amyloid formation, we designed inhibitors of fibrillogenesis. We hypothesized that amyloid formation could be inhibited by short Ab homologous peptides bearing b-sheet blocker residues (anti-b-sheet peptides). Anti-b-sheet peptides designed according to these principles inhibited Ab amyloid formation, dissolved preformed fibrils in vitro, and blocked amyloid deposition in an animal model of amyloidosis. These results may prove to be a novel therapeutic approach for preventing or retarding amyloid formation implicated in AD pathology.

Model for the physiological and pathological Ab conformers, the factors involved in the interconversion between them and the properties associated to each conformational state.

Representative Publications:

• Soto C, Braes MC, Alvarez J and Inestrosa NC. Structural determinants of Alzheimer's amyloid b-peptide. J Neurochem 63 1191-1198 (1994)
• Soto C, Castao EM, Frangione B and Inestrosa NC. The a-helical to b-strand transition in the amino-terminal fragment of the amyloid b-peptide modulates amyloid formation. J Biol Chem 270 3063-3067 (1995)
• Soto C and Frangione B. Two conformational states of amyloid b-peptide implications for the pathogenesis of Alzheimer's disease. Neurosci Lett 186 115-118 (1995)
• Soto C, Golabek A, Wisniewski T and Castao EM. Alzheimer's b-amyloid peptide is conformationally modified by apolipoprotein E in vitro. Neuroreport7 721-725 (1996)
• Soto, C and Castao, EM. The conformation of Alzheimer's b-peptide deturmines the rate of amyloid formation and its resistance to proteolysis. Biochem J 313 701-707 (1996)