Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease

Table 2 Phenotypes of common amyloid precursor protein mutations

APP mutation	Aβ generation	AICD generation	AICD/ε-cleavage quantifi cation	Reference
KM670/671NL (Swedish)	Total Aβ ↑ in transfected cells (6- to 8-fold) and human FAD fi broblasts (3-fold)	ND	ND	[35–37]
Various 717	Aβ42 ↑ (1.5- to 1.9-fold)	ND	ND	[47]
T714I, V715M, I716F, V717I, V717F, V717G	Aβ42/40 ↑ for V717I, others ND	AICD →	C99 luciferase reporter	[45]
T714I, V715M, I716V, V717I, V717L, L723P	All mutants Aβ42/Aβ40 ↑	T714I: AICD ↓ L723P: AICD ↓ V715M: AICD ↑ I716V: AICD ↑ V717I: AICD → V717L: AICD →	Immunodetection of AICD after in vitro generation in membranes (APP Swedish combined with second mutant)	[46]
T714I	Aβ42/Aβ40 ↑ (11-fold)	ND	ND	[113]
V715F	Aβ40 and Aβ42 ↓ Aβ38 ↑	AICD →	Immunodetection of AICD after in vitro generation in membranes	[123]
E693Q Dutch	Aβ →	ND	ND	[23]
A692G Flemish	Aβ40 and Aβ42 ↑	ND	ND	[23, 24]
E693G Arctic	Aβ42 ↓	ND	ND	[26]
A673V (recessive)	Aβ40 and Aβ42 ↑ Aggregation and fibril formation ↑ in homozygous carriers, but anti-amyloidogenic in heterozygous	ND	ND	[105]

Note that immunoassays discriminating Aβ40 and Aβ42 became available in 1994 [46] and any prior data are based on immunoprecipitation of ³⁵S-methionine labeled total Aβ. ε-Cleavage leading to AICD formation was discovered in 2001 [48]. Up arrows indicate increase; down arrows indicate decrease; right-pointing arrows indicate no change compared to WT APP. Aβ, amyloid-β; AICD, amyloid precursor protein intracellular domain; APP, amyloid precursor protein; ND not determined.

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