Nonfibrillar diffuse amyloid deposition due to a γ42-secretase site mutation points to an essential role for N-truncated Aβ42 in Alzheimer's disease

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition 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 generally believed that nonfibrillar pre-amyloid A beta (42) deposits have to mature in the presence of AP(40) into fibrillar amyloid plaques to cause neurodegeneration, Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T7141) directly involving gamma -secretase cleavages of APP, The mutation had the most drastic effect on A beta (42)/A beta (40) ratio in vitro of similar to 11-fold, simultaneously increasing A beta (42) and decreasing AP(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry, This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta (42) in complete absence of A beta (40) These data indicate that N-truncated A beta (42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology, importantly, inhibiting secretion of full-length A beta (42) by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta (42).