Supplementary Table 1 Levels of proteolytic fragments from disease associated APPmutations in various experimental systems
Measures reported as relative values are shown as qualitative change; absolute values given with units as reported, Y-reported only as present.
Mutation position / Comments / APP / [sAPP] / sAPPα / sAPPβ / CTFα C83 / CTFβ C99 / C99/ C83 / [Aβ] / Aβ40 / Aβ42 / Aβ42/40 / Aβ’ / Aβ<40 / Oligo / Fibril / P3 / AICD / Experimental system / N / RefKM670/671NL Swedish / Normalised to full length APP / ↓ / Aβ / ↑ / ↑ / ↑x5 / M17 cell culture / 3 replicates / [1, 2]
Not significantly different to WT / 14.5 ± 3.3 ng/ml / Human CSF / (4 AD, 2 pre-symptomatic / [3]
↑ / ↑ x2.2 / Rat hippocampal neurons / 3 replicates / [4]
↑ / ↑ 18,653 ±1759 pg/ml / ↑ 1,380 ±47 pg/ml / ↓ 7.4 ±0.5 % / HEK293 / 4 replicates / [5]
↑ / ↑ x6-8 / ↓ / HEK293, CHO cell culture / 4 replicates / [6]
↑ / ↑ / ↓ / Human fibroblasts / 5 cell lines / [7]
Longer forms of APP increased but not APP695 / ↑ / ↑x~2.7 / Human fibroblasts / 3 cell lines; at least 6 measures / [8]
=
518 ±33 ng/ml / ↑41.4 ±5.1 ng/ml / ↑3.11 0.69 ng/ml / 293T / 3 replicates one experiment / [9]
↑675±59 fmol/ml / ↑59.1±4.9 fmol/ml / 8.8±0.9 % = / HEK293 cells / Not given / [10]
% of control / ↑ / ↓ / No change / ↑ / ↑ / ↑ / ↑ / no change / HEK293 cells / 3 or 4 replicates / [11]
% of control / ↑482% / TSM1 neurons / 4 / [11]
↑ / ↑57 ±3 / 67 ±10 pmol / Human plasma / 7 pre-symptomatic/ 5 AD / [12]
A673T / ↑ 564 ±21 ng/ml / ↓50% 8.1 ±0.7 ng/ml / ↓ 40% / 1.5 ±0.1 ng/ml / 0.14 ±0.02 ng/ml / ↓ / 293T / 3 replicates from one experiment / [13-15]
Normalised to human full length APP / ↓0.65±0.14 M / ↓0.81 ±0.21 M / ↓0.001±0 M / ↓0.27±0.02 M / ↓ / ↓~2 ng/ml / ↓~0.2 ng/ml / Aβ40↓ Aβ42= / Primary neurons / 3 replicates from 3 experiments / [16]
A673V / Increased Aβ40 (not Aβ42) fibrils; amyloid deposits contain both Aβ40 and Aβ42; large plaque size and vessel association; homozygous only / ↓ 476 ±2 ng/ml / ↑ 51.5 ±4.4 ng/ml / ↑ 10.4 ±0.7 ng/ml / ↑ 0.72 0.08 ng/ml / 293T / 3 replicates from one experiment / [13, 16-21]
Normalised with respect to human full lengthAPP / 0.92±0.12 M = / ↓0.31±0.07 M / ↑1.02±0.02 M / ↑1.04±0.02 M / ↑ / ↑~8 ng/ml / ↑~0.9 ng/ml / Aβ40↑ Aβ42= / Primary neurons (Mouse) / 3 replicates 3 experiments / [16]
Heterozygotes showed slower fibrillogenesis compared to wt; Aβ42 faster than Aβ40 / ↓151 pg/ml / human CSF / 1 AD / [17]
↑426.5 pg/ml / ↑45.9 pg/ml / human plasma / 1 AD / [17]
2.5 fold increase in sAPPβ:sAPPα ratio; normalized to the number of cells / ↑x2.5 / ↑20.2 pg/ml / ↑2.9pg/ml / 0.1 No change / Human fibroblasts / 4 replicates / [17]
Normalised to full length APP signal intensity / ↑ / ↑ x1.9 ±0.2 / ↑85.3 ±8.6 pg/ml / ↑9.9 ±1.3 pg/ml / 0.1 No change / ↑ Aβ11-40 27.3 ±2.4, Aβ11-42 45.7 ±8.4 / ↑ / CHO cells / 7 replicates / [17]
↑863.4 ±32.6 pg/ml / ↑78.1 ±22.9 pg/ml / 0.1 No change / ↑ Aβ11-40 233.8 ±16.6, Aβ11-42 198.5 ±6.6 / COS7 cells / 7 replicates / [17]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
H677R English / [23]
No change / No change / No change / No change / HEK293 cells / 6 replicates / [24]
D678H Taiwanese / Normalised to WT / No change / ↑ / ↑ / ↑ x10.3 / ↑ x1.5 / ↑ x2.4 / ↑ / Aβ40↓ Aβ42↑ / Aβ40↑ Aβ42↓ / HEK293 cells / 3 replicates / [25]
Increased full length APP via lysosome; novel FAD mechanism relevant to SAD / ↑ / ↑ / ↑ / ↑ / HEK293 cells / 6 replicates / [24]
D678N Tottori / No change / No change / No change / No change / HEK293 cells / 6 replicates / [24, 26]
E682K Leuven / Shifts β’ to β-pathway processing / ↑ x2±3 / ↑ x2±3 / ↑ / ↑ 604.6 pg/ml / ↑ 94.6 pg/ml / ↑ / ↓ / No change / No change / CHO cell culture / 3 / [27]
Normalised to full length APP; β'-cleavage C89 ~24% CTFs / ↑ / ↑ x2±3 / No chamge / ↑ x2±3 / ↑ / ↑ 1005.3 ±10.1 pg/ml / ↑ 189.9 ±5.1 pg/ml / ↑ / ↓ / No change / No change / Primary neurons / 3 / [27]
Normalised to full length APP / 986±255.8 /368±63.7 /165 pg/ml / No change / No change / human CSF / 7 controls/ 10 AD/ 1 FAD / [27]
K687N / Equimolar WT + mutant Aβs increase toxicity than either WT or mutant homo-oligomers / ↓ / human CSF / 1 mutation carrier / [28, 29]
Normalised to full length APP WT; increased Aβ37/38/39 / ↑ / ↓ 40±50% / ↓ 50% / ↓ 75% / ↓ x2 / ↑ / ↑ 50% / ↑ 50% / ↑ / ↑ / ↓ / HEK293 cells / 4-6 replicates / [28]
A692G Flemish / Plaques centred on vessels; mostly Aβ40 in cored amyloid deposits, diffuse amyloid deposits Aβ42; severe NFT pathology / Human brain tissue IHC and MALDI-TOF / 3 AD with APPmutations, 5 SAD, 3 AD with PSENs mutations, 1 HCHWA-D / [30-32]
Normalised to APP synthesis / ↑ 647±120.4 / ↑ 45.2±9.2 / ↑ 7.0±0.8 / CHO K1 / 3 measures from 2 replicates / [33]
Normalised to APP synthesis / ↑231.7 ±40.2 / ↑ 29.7±5.2 / ↑12.8±0.09 / HEK293 cells / 3 measures from 2 replicates / [33]
Normalised to APP synthesis / ↑ 23.4±0.3 / ↑ 2.6±0.2 / ↑ 10.9±0.8 / H4 / 3 measures from 2 replicates / [33]
Normalised to cellular APP / ↑ / ↑ x1.7 / Rat hippocampal neurons / 3 / [4]
Normalised to full length APP / ↑ / ↑621.3 ±27.2 pg/ml / ↑77.5 ±2.4 pg/ml / ↑ 0.1251±0.0039 / CHO / 3 / [27]
Normalised to full length APP / ↑ / ↑1049.2 ±42.7 pg/ml / ↑131.7 ±1.5 pg/ml / ↑ 0.1257 ±0.0037 / Primary neurons / 3 / [27]
A692G Flemish / ↑232.0±25 fmol/ml / ↑27.0±2.0 fmol/ml / ↑11.7±1.6 % / HEK293 cells / [10]
Percent of Aβ-type fragments / ↑33 / ↑16.6 / ↓50.5 / HEK293 cells / 3-9 replicates / [34]
Relative to WT / No change / No change / No change / ↑x2.3 / 4 replicates / [35]
ΔE693 E693del Osaka / Very low levels of amyloid on PiB MRI / [5, 36]
Aβ in mitochondria and ER; ER stress induced apoptosis / ↑ / COS7 cells / [36]
More resistant to degradation by Neprilysin and IDE / ↓ / ↓ 390 pg/ml / ↓ 22 pg/ml / ↓ (5.7) / ↑ / None / Human CSF / 5 AD, 12 other neurological disorders / [5]
↓ / ↓495±18 / ↓54±6 / No change / ↑ / None / HEK293 cells / 4 replicates / [5]
E693K Italian / No NFT; capillary CAA / [37, 38]
↓126±17 / ↓8.0±0.7 / ↓6.4±0.6 / Hek293 cells / Not given / [10]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
E693Q Dutch / No NFT / [39-42]
Normalised to APP synthesis / ↓ 258±93.3 / ↓ 12.7±4.5 / ↓4.9±0.3 / CHO K1 / 3 measures from 2 replicates / [33]
Normalised to APP synthesis / ↓176.7±20.5 / ↓10.6±1.2 / ↓6±0.03 / HEK293 cells / 3 measures from 2 replicates / [33]
Normalised to APP synthesis / ↓ 10.7±0.7 / ↓ 0.7±0.1 / ↓ 6.6±0.9 / H4 / 3 measures from 2 replicates / [33]
147±12= fmol/ml / ↓9.6±0.7 fmol/ml / ↓6.6±0.6 % / HEK293 cells / Not given / [10]
Relative to WT / No change / No change / No change / No change / H4 cells / 4 replicates / [35]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
E693G Arctic / Increased formation of Aβ40protofibrils / [43, 44]
Severe CAA, typical AD NFT, abundant amyloid plaques reactive with Aβ40 and Aβ42 / 2 AD / [44]
↓~100 fmol/ml / ↓~12 fmol/ml / Human plasma / 9 mutation carriers / [10]
149±3 = fmol/ml / ↓11.2±0.6 fmol/ml / ↓7.5±0.5 % / HEK293 cells / [10]
Compared to WT; Soluble Aβ oligomers caused neuronal death / ↑ / rat cortical neuron cultures / 4 replicates / [45]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
D694N Iowa / Increased Aβ40 in diffuse plaques; NFTs and activated microglial in vessels / [46, 47]
Relative to WT / No change / No change / No change / No change / H4 cells / 4 replicates / [35]
L705V Italian / No amyloid plaques or tangles; vessels show both Aβ40 and Aβ42 / [48]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
G709S / Shifts Aβ profile from Aβ40 to Aβ39 Aβ37 / ↓ / ↑ / HEK293 cells / [49]
A713T / Abundant NFT and plaques / No change / [50-54]
Heterozygous and homozygous; no dose effect / ↓ / ↑ / ↑ / Human plasma / 2 measures from 10 mutation carriers (2 homo- and 8 heterozygotes) 2 related non mutation carriers / [53]
↑Aβ38 / Human brain / 10 FAD with APP mutations, 6 FAD with PSEN1 or PSEN2 mutations, 4 DS, 12 SAD, 3 controls / [22]
A713V / [55, 56]
T714A Iranian / Long prodromal phase, epilepsy and autonomic failure / ↓193 pg/ml / Human CSF / [19, 57-60]
T714I Austrian / Diffuse amyloid plaques N-truncated Aβ; cored plaques and vessel walls full length Aβ; severe NFT neuronal loss and gliosis / Human brain tissue / 1 AD / [61-63]
Changes in P3 mirror Aβ; increase Aβ N-terminal truncation / No change / No change / ↓68% / ↑x3.5 / ↑x10.8 / HEK293T cells / 3 replicates / [61]
Normalised with respect to WT / ↑ / ↑ / ↓~20% / ↑ / ↑x8.20 / Primary neurons / 3-10 replicates / [64]
V715M French / Reduced [Aβ] due to Aβ40; no change in Aβ42; % of control / ↑ / ↑ / ↑ / no change / ↓ / ↓ / No change / ↑ / present / present / present / HEK293 cells / 3 or 4 replicates / [11, 65, 66]
% of control / ↓~75% / TSM1 neuronal cells / 8 / [11]
Normalised to WT / No change / No change / ↓~30% / No change / ↑ / Primary neurons / 3 replicates / [64]
V715A German / Increased Aβ42/Aβ40 ratio / [23, 58, 67]
Normalised to WT / No change / No change / ↓~55% / ↑ / ↑ / Primary neurons / 3-10 replicates / [64]
I716V Florida / 92.5 ± 3.0 pmol = / ↑13.5 ± 1.1 pmol / ↑14.6 ± 0.7 % / HEK293 cells / 2 wells in duplicate / [68]
↑138.7 ± 1.3 pmol / ↑19.8 ± 1.5 pmol / ↑14.3 ± 1.0 % / CHO cells / 2 wells in duplicate / [68]
Normalised to WT / ↓ / No change / No change / ↑ / ↑ / Primary neurons / 3-10 replicates / [64]
Normalised to Total Aβ / No change / x1.14 ±0.16 = / ↑x1.91 ±0.18 / 1.73 ±0.20 = / Aβ38↑x3.13 ±0.43 / No change / CHO cells / 3 replicates / [69]
No change / No change / Human H4 cells / [69]
I716F / Increased APP [CTF]; values relative to WT; reduced γ- and ε cleavages / ↓x0.5 / ↓x0.5 / ↑x2 / ↑x4 / ↓ / CHO cells / 3 replicates / [54, 70-72]
No change / ↓x0.12 ±0.03 / ↑x2.45 ±0.34 / ↑21.91 ±1.85 / ↓to 40.3% / CHO cells / 3 replicates / [69]
↑ / ↑ / Human H4 cells / [69]
Numerous plaques, CAA, NFT braak stage VI, N-truncated pyroglutamate Aβ, A/syn Lewy bodies, vascular and small cored amyloid plaques reactive for Aβ oligomers / ↑ / 1 / [72]
Intracellular Aβ; normalised to WT / No change / ↓0.15 ±0.05 / ↑2.37 ±0.4 / ↑18 ±3.6 / CHO cells / 3 replicates / [73]
I716T / [74]
No change / ↓x0.22 ±0.03 / ↑x2.69 ±0.30 / ↑x12.35 ±0.51 / Aβ38↑x3.44 ±0.59 / No change / CHO cells / 3 replicates / [69]
No change / No change / Human H4 cells / [69]
V717I London / Numerous amyloid plaques and NFT, variable CAA / [23, 65, 75-79]
Normalised to full length APP / ↓ / No change / ↓ / M17 / 3 replicates / [77]
Normalised to APP synthesis / ↓ 126.7±5.2 / ↑ 23.8±2.8 / ↑ 18.9±2.1 / CHO K1 / 3 measures from 2 replicates / [33]
Normalised to APP synthesis / ↓ 119.6±19.6 / ↑ 27.4±4.5 / ↑ 22.9±1.0 / HEK293 cells / 3 measures from 2 replicates / [33]
Normalised to WT / ↑ / ↑ / ↓ / ↑ / ↑x1.89 / Primary neurons / 3-10 replicates / [64]
↓68.6 ± 1.9 pmol / ↑11.4 ± 1.9 pmol / ↑16.6 ± 2.4 % / HEK293 cells / 2 wells analysed in duplicate / [68]
54.1 ± 1.3 pmol = / ↑9.5 ± 0.5 pmol / ↑17.5 ± 0.5 % / CHO cells / 2 wells analysed in duplicate / [68]
Increased APP [CTF]; reduced γ-secretase activity; values relative to WT / ↓ / ↓ / ↑ / ↑ / ↓ / CHO cells / 3 replicates / [70]
↑>650 pmol / ↑47 pmol / Human Plasma / 1 AD / [12]
↓0.58 ±0.09 / 0.99±0.4 = / ↑1.8 ±0.57 / CHO cells / 3 replicates / [73]
↑x1.8 / HEK293 cells / [61]
V717L Indiana / ↓ / ↑ / ↑ / [80-83]
Normalised to WT / ↑ / ↑ / ↓ / ↑ / ↑ / Primary neurons / 3-10 replicates / [64]
V717F Indiana / Increased Aβ42/Aβ40 ratio / [81, 84]
↓89±11 fmol/ml / ↑24.4±2.4 fmol/ml / ↑27.4±1.4 / HEK293 cells / [10]
V717G / [85, 86]
T719P / Reduced total Aβ Aβ1−40 Aβ1−42 with increase d
Aβ10−40 Aβ1−38 / ↓ / ↓ / ↓ / ↓ / ↓ Aβ11x ↑Aβ10x / ↓ / Human CSF / 1 APP p.T719P FAD, 10 controls, 2 PSENs FAD / [87]
L723P Australian / Increase in apoptosis relative to WT / ↑x1.9 ±0.8 / ↑x2 / CHO cells / Pooled conditioned media from several clones / [88]
K724N Belgian / No change / No change / ↓~30% / ↑x2 / ↑x2.6 / Aβ38 & Aβ39↑ Aβ37= / HEK293T cells / [89]
H733P / [71]
APP
duplication / Duplication size varies ; may not always be fully penetrant
Aβ42 reduced in CSF / ↓ / Human CSF / 4 familial and 1 sporadic APP duplication / [90]
Duplication of APP +15 other genes; Braak stage VI, Aβ plaques and CAA / ↑x1.5 / Human comparative / 5 families with early onset FAD / [91]
Several genes duplicated; AD pathology with CAA and ICH; strong intraneuronal Aβx-40 accumulation in CA1/2 hippocampal fields; increased presence of seizures similar to DSbut without DS clinical features / ↑ / Human case-control / 14 patients with APP duplication, 5 with detailed neuropathological characterisation / [92]
APP only duplicated;AD pathology and CAA; increased presence of seizures similar to DS / ↑ / ↑ / Human observational study / 111 early onset FAD / [93]
APP duplications not always fully penetrant / No Change / Epstein-Barr virus–transformed lymphoblastoid cells / 3 affected family members / [82]
APPpromoter mutations / Promoter region mutations can lead to variable increases in APP levels; some are similar to DS and APP duplication / [79, 94]
DS / Increased levels of APP – not all DS cases develop dementia / ↑ / [95-97]
Complex changes in levels of Aβ species; Aβ40 levels while initially higher in DS are reduced with DS dementia; Levels of Aβ42 and Aβ42/Aβ40 are initially lower but increase with DS dementia / [98]
Aβ: amyloid beta protein, AD: Alzheimer disease, APP: amyloid beta precursor protein, CAA: cerebral amyloid angiopathy, CTF: carboxy terminal fragments, DS: Down syndrome, ICH: intra-cerebral haemorrhage, NFT: neurofibrillary tangles, SP: senile plaques (amyloid), WT: wild type
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