Table 1 Evidence that APOE4 is a loss of positive or gain of negative function: comparison to absence of APOE

Behavior/cognition

Loss of function

5xFAD/APOE-KO, EFAD

Postsynaptic protein levels

Loss of function

NMDAR subunits

Loss of function

p-CaMK-II levels

Loss of function

p-CREB levels

Gain of toxic function

BDNF levels

Gain of toxic function

Measure

apoE4 represents:

Mouse model

Reference

Anti-inflammatory

Loss of function

APOE-KO, APOE-TR

[47]

Baseline LTP

Loss of function

WT, APOE-KO, APOE-TR (Ex vivo hippocampal slice cultures)

[50]

Amyloid deposition

Loss of function

APOE-KO x APP^V717+/-

[118],

APP^V717+/- x GFAP-apoE^+/-

[119,120],

5xFAD, EFAD

[48]

for review, [35]

ApoE lipidation

Loss of function

APOE-TR

[121]

EFAD

[58]

Dendritic spine density

Loss of function

WT, APOE-KO, GFAP-apoE^+/+

[84]

BBB integrity

Loss of function

WT, APOE-KO, APOE-TR, GFAP-APOE

[122]

Aβ clearance across the BBB

Loss of function

WT, APOE^+/-, APOE-KO

[123]

Behavior/cognition

Gain of toxic function

WT, APOE-KO, APOE-TR

[33]

WT, APOE-KO, APOE-TR

[34]

WT, APOE-KO, GFAP-apoE

[124]

WT, APOE-KO, GFAP-apoE (female)

[125]

WT, APOE-KO, NSE-apoE

[124,126]

Accumulation of intraneuronal oAβ

Gain of toxic function

APOE-KO, APOE-TR

[127]

oAβ-induced neurotoxicity

Gain of toxic function

WT, APOE-KO, APOE-TR

[52]

In vitro neuron/glial co-cultures

oAβ-dependent inhibition of LTP

Gain of toxic function

APOE-KO, APOE-TR

[51]

Neurotoxicity of apoE proteolytic fragments

Gain of toxic function

Variety with APOE-KO control

[75,128] for review, [129]

Neurite outgrowth

Loss of function

APOE-KO olfactory epithelia cultures (exogenous apoE added) APOE-KO

[130]

Gain of toxic function

cortical neuron cultures (exogenous apoE added)

[131]