Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease

Amyloidogenic processing of the amyloid precursor protein (APP) with deposi tion in brain of the 42 amino acid long amyloid P-peptide (A beta (42)) is considered central to Alzheimer's disease (AD) pathology. However, it is ge nerally believed that nonfibrillar pre-amyloid A beta (42) deposits have to mature in the presence of AP(40) into fibrillar amyloid plaques to cause n eurodegeneration, Here, we describe an aggressive form of AD caused by a no vel missense mutation in APP (T7141) directly involving gamma -secretase cl eavages of APP, The mutation had the most drastic effect on A beta (42)/A b eta (40) ratio in vitro of similar to 11-fold, simultaneously increasing A beta (42) and decreasing AP(40) secretion, as measured by matrix-assisted l aser disorption ionization time-of-flight mass spectrometry, This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyl oid plaques composed primarily of N-truncated A beta (42) in complete absen ce of A beta (40) These data indicate that N-truncated A beta (42) as diffu se nonfibrillar plaques has an essential but undermined role in AD patholog y, importantly, inhibiting secretion of full-length A beta (42) by therapeu tic targeting of APP processing should not result in secretion of an equall y toxic N-truncated A beta (42).