CROSS-LINKING OF BETA-AMYLOID PROTEIN-PRECURSOR CATALYZED BY TISSUE TRANSGLUTAMINASE

Alzheimer's disease is characterized by progressive dementia, cortical atrophy with synaptic loss, and the accumulation of neurofibrillary t angles and senile plaques containing beta-amyloid. The beta-amyloid pr otein precursor (beta-APP), may normally be involved in cell adhesion related to synaptic maintenance. Loss of synapses correlates with deme ntia, suggesting that synaptic deficits may underlie the disease. Syna pse stability may depend on the action of tissue transglutaminase (tTG ), an enzyme capable of crosslinking large, multi-domain extracellular glycoproteins, that is active and present at synapses. We now show th at beta-APP is a substrate for tTG in vitro that results in dimers and multimers by silver staining and immunoblotting. This novel post-tran slational modification suggests further roles for beta-APP in synaptic function as well as in Alzheimer's disease.