Major Carboxyl Terminal Fragments Generated by γ-Secretase Processing of the Alzheimer Amyloid Precursor Are 50 and 51 Amino Acids Long

Based on findings that the FAD mutation that increases Aβ42 also reduces AICD, we propose that γ-secretase activity is impaired by FAD mutations and predict that physiologic and environmental agents that inhibit γ-secretase will actually induce AD pathogenesis rather that prevent it. Furthermore, we propose that the cleavage site to generate AICD is naturally ragged and occurs predominantly at two sites 48 and 49 aa from the start of the Aβ sequence. Thus, end specific antibodies to these two sites will need to be generated to study the quantitative relationships between these two cleavages in sporadic AD and FAD.