Skip to main content

Table 3 γ-Secretase-dependent phenotypes of presenilin mutations

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

Model system

Aβ40

Aβ42

Aβ42/Aβ40

AICD

NICD

N-cadherin

Other phenotypes

Reference

PSEN1-M146L

        

Overexpression (HEK293, CHO)

→

↑

↑

ND

ND

↓

-

[79, 80, 83]

Overexpression (PSEN-/-)

ND

ND

ND

ND

→

ND

-

[81]

Kinetic in vitro assay

→

↑

↑

ND

ND

ND

-

[83]

Transgenic mice

ND

↑

↑

ND

ND

ND

Total Aβ →

[74]

PSEN1-L166P

        

Overexpression (HEK293)

↓

↑

↑

↓

↓

ND

-

[80]

Overexpression (PSEN-/-)

↓

→

↑

↓

↓

↓

APP-CTFs ↑

[64]

PSEN1-I213T

        

Overexpression (PSEN-/-)

↓

↓

↑

ND

ND

ND

APP-CTFs →

[123]

Kinetic in vitro assay

↓

→

↑

ND

ND

ND

-

[84]

Knock-in mice (heterozygous)

→

↑

↑

ND

ND

ND

-

[67]

PSEN1-R278I

        

Knock-in mice (heterozygous)

↓a

→

→

→

→

→

APP-CTFs →

[68]

Primary cells (from knock-in mice)

↓

→

↑

ND

→

ND

Total Aβ →

Aβ43 ↑

[68]

Kinetic in vitro assay

↓

↓

ND

↓

ND

ND

Total Aβ ↓

[68]

PSEN1-A246E

        

Overexpression (PSEN-/-)

→

→

↑

↓

→

→

APP-CTFs →

[64, 81]

Transgenic mice

→

↑

↑

ND

ND

ND

-

[124]

Primary cells

↑

↑

↑

ND

ND

ND

-

[70, 125]

PSEN1-ΔExon9

        

Overexpression (HEK293)

→

↑

↑

↓

↓

↓

-

[78–80]

Overexpression (PSEN-/-)

↓

→

↑

↓

↓

↓

APP-CTFs ↑

[64, 81]

Transgenic mice

→

↑

↑

ND

ND

ND

-

[124]

PSEN1-G384A

        

Overexpression (HEK293, CHO)

↓→

→

↑

ND

ND

↓

-

[79, 80, 83]

Overexpression (PSEN-/-)

↓→

→

↑

↓

↓

↓

APP-CTFs →

[64, 75, 107]

Kinetic in vitro assay

↓

→↑

↑

↓

ND

ND

Total Aβ ↓

[82, 83]

PSEN1-C410Y

        

Overexpression (PSEN-/-)

↓

↓

↑

ND

↓

ND

APP-CTFs ↑

[75, 81, 123]

PSEN2-N141I

        

Overexpression (COS-1, N2a, CHO)

↓

↑

↑

ND

ND

ND

-

[83, 126]

Overexpression (PSEN-/-)

↓

↑

↑

↓

↓

↓

APP-CTFs →

[64, 65]

Kinetic in vitro assay

↓

↑

↑

ND

ND

ND

-

[83]

Transgenic mice

↓

↑

↑

ND

ND

ND

-

[127, 128]

Primary cells

→↑

↑

↑

ND

ND

ND

-

[70, 125]

  1. PSEN mutations were chosen based on their investigation in multiple independent studies and model systems. All phenotypes of the PSEN mutants are reported in comparison to WT PSEN1. Studies that did not include a WT PSEN control condition are not included in this table. Up arrows indicate increase; down arrows indicate decrease; right-pointing arrows indicate no change compared to WT PSEN. Two arrows next to each other indicates that two or more studies reported different results compared to WT PSEN. Increased APP-CTFs, which are the immediate substrates of γ-secretase, can be interpreted as a sign of reduced enzyme activity. N-cadherin processing by γ-secretase was assessed in the studies by Bentahir and colleagues [63], Marambaud and colleagues [78] and Saito and colleagues [67] in different ways. However, in all cases a decrease indicates reduced processing of N-cadherin and diminished formation of the N-cadherin intracellular domain. aThe reduction in endogenous mouse Aβ40 steady-state levels in brain of heterozygous knock-in mice for the PSEN1-R278I mutation was only observed in the guanidine-HCL but not in the Tris-HCL-buffered saline soluble fraction. Aβ, amyloid-β; AICD, amyloid precursor protein intracellular domain; APP, amyloid precursor protein; CHO, Chinese hamster ovary; CTF, carboxy-terminal fragment; ND, not determined; NICD, NOTCH intracellular domain; PSEN, presenilin; WT, wild type.