Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo

Q: What are the key findings of this study?

Endothelial cell APOE4 knockdown impaired trace fear memory extinction, increased cortical IgG permeability by ~17%, and disrupted cortical E-I synaptic balance.

Q: What is the clinical evidence from this study?

Population: Endothelial APOE4 regulation of neurovascular and neural function. Intervention: Endothelial cell APOE4 knockdown (APOE4 fl/fl /Cdh5(PAC)-CreERT2 +/-) vs. Control APOE4 fl/fl /Cdh5(PAC)-CreERT2 -/- mice receiving identical tamoxifen injections. Primary outcome: Trace fear memory extinction index (EI) (F(1, 33) = 17.578, p=<0.001).

Q: What does this research mean for the field?

Endothelial cell APOE4 knockdown impairs trace fear memory extinction, increases cortical neurovascular permeability, and disrupts cortical excitatory-inhibitory synaptic balance in vivo. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Q: What question did this study set out to answer?

To determine whether endothelial cell APOE4 is detrimental or protective for neurovascular and neural function in vivo under physiological conditions.

Felecia M. Marottoli; Deebika Balu; Edén Flores-Barrera; Emilce Artur de la Villarmois; Hui Zhang; Rohan Jagat Chaudhary; Ruju Talati; Kuei Y. Tseng; Leon M. Tai

doi:10.1161/jaha.124.035080

November 29, 2024Journal of the American Heart AssociationOpen Access

Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo

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Key result

Endothelial APOE4 knockdown impairs fear memory extinction, lowering extinction index by ~38 percentage points.

F(1, 33) = 17.578
P<0.001

Figures

Why the study?

Whether endothelial APOE4 is detrimental or protective for neural function under physiological conditions was unknown.

Does conditional knockdown of endothelial cell APOE4 dysregulate neurovascular integrity, prefrontal cortical synaptic activity, and fear memory extinction in vivo in mice expressing human APOE4?

Key Points

To determine whether endothelial cell APOE4 is detrimental or protective for neurovascular and neural function in vivo under physiological conditions.
Generated APOE4 fl/fl /Cdh5(PAC)-CreERT2 +/- and APOE4 fl/fl /Cdh5(PAC)-CreERT2 -/- (control) mice.
Induced endothelial APOE4 knockdown at ≈4 to 5 weeks of age using tamoxifen.
Evaluated neurovascular integrity, fear extinction behavior, synaptic protein levels, and cortical electrophysiology at 9 months of age.
Endothelial APOE4 knockdown caused higher cortical neurovascular permeability, with ≈17% higher IgG levels, a trend toward higher fibrinogen (≈20%, P <0.1), and ≈10% lower claudin-5 vessel coverage.
Knockdown mice exhibited impaired trace fear memory extinction, taking longer to initiate extinction and reaching an extinction index of 31% compared with 69% in controls.
Electrophysiology in cortical pyramidal neurons revealed marked excitatory-inhibitory imbalance (E/I=0.55), driven by enhanced inhibitory synaptic event frequency and reduced excitatory events.

Structured PICO

Does conditional knockdown of endothelial cell APOE4 dysregulate neurovascular integrity, prefrontal cortical synaptic activity, and fear memory extinction in vivo in mice expressing human APOE4?

P

Population

Male and female humanized APOE4 fl/fl /Cdh5(PAC)-CreERT2 mice with endothelial cell APOE4 knockdown induced at 4 to 5 weeks of age and evaluated at 9 months of age.

I

Intervention

Conditional endothelial cell APOE4 knockdown induced at 4 to 5 weeks of age via intraperitoneal tamoxifen injection (20 mg/mL in corn oil, 100 μL every 24 hours for 5 days) in APOE4 fl/fl /Cdh5(PAC)-CreERT2 +/- mice.

C

Comparator

Control APOE4 fl/fl /Cdh5(PAC)-CreERT2 -/- littermate mice receiving identical intraperitoneal tamoxifen injections (20 mg/mL in corn oil, 100 μL every 24 hours for 5 days) at 4 to 5 weeks of age.

O

Outcome

Neurovascular and neuronal function at 9 months of age, assessed by trace fear memory extinction index (EI), cortical plasma protein permeability (IgG and fibrinogen), claudin-5 vessel coverage, and prefrontal cortex layer V pyramidal neuron excitatory-inhibitory (E-I) postsynaptic current ratio.surrogate

Main Result

Effect estimate: F(1, 33) = 17.578

Absolute Event Rate: 31% vs 69%

p-value: p=<0.001

Endothelial cell APOE4 is protective rather than toxic for neurovascular integrity, prefrontal synaptic balance, and cognitive behavior in vivo when other cell types express APOE4, suggesting therapeutic strategies should avoid depleting endothelial apoE4.

Limitations

APOE4 was knocked down in all endothelial cells rather than specifically only brain endothelial cells
APOE3 was intentionally omitted as the focus was comparing endothelial APOE4 to its null condition
Timing of APOE4 knockdown (4 to 5 weeks of age) may affect whether APOE4 acts as a loss of positive function
Lack of additional assays for different neurovascular functions, astrocyte functions, and apoE levels in other central nervous system cell types
APOE4 was knocked down in all endothelial cells rather than exclusively brain endothelial cells
Direct comparison with APOE3 was omitted
Timing of APOE4 knockdown may influence whether APOE4 manifests as a loss of positive function
Lack of additional assays for other neurovascular functions, astrocyte functions, and apoE levels in other CNS cell types

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Implication

Endothelial APOE4 supports memory extinction and barrier integrity in APOE4 mice; leaves open whether preserving it benefits humans.

Abstract

Background We recently found that loss of endothelial cell APOE3 disrupts neurovascular and synaptic function. However, whether endothelial APOE4 is detrimental or protective for neural function under physiological conditions is unknown. Therefore, the goal of this study was to determine the role of endothelial cell APOE4 in regulating brain function in vivo. Methods and Results We developed APOE4 fl/fl /Cdh5(PAC)‐CreERT2 +/− and APOE4 fl/fl /Cdh5(PAC)‐CreERT2 −/− (control) mice. Knockdown of endothelial cell APOE4 was induced at ≈4 to 5 weeks of age. Experiments were conducted at 9 months of age to evaluate neurovascular and neuronal function via biochemistry, immunohistochemistry, behavior tests, and electrophysiology. Endothelial cell APOE4 knockdown resulted in higher neurovascular permeability, lower claudin‐5 vessel coverage, impaired trace fear memory extinction, and disruption of cortical excitatory‐inhibitory balance of synaptic activity. Conclusions Our data support the novel concept that endothelial cell APOE4 is protective for brain function when other cell types express APOE4 .

Discussion

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Cite This Study

Marottoli et al. (2024) studied Endothelial APOE4 regulation of neurovascular and neural function. Endothelial cell APOE4 knockdown (APOE4 fl/fl /Cdh5(PAC)-CreERT2 +/-) vs. Control APOE4 fl/fl /Cdh5(PAC)-CreERT2 -/- mice receiving identical tamoxifen injections was evaluated on Trace fear memory extinction index (EI) (F(1, 33) = 17.578, p=<0.001). Endothelial cell APOE4 knockdown impaired trace fear memory extinction, increased cortical IgG permeability by ~17%, and disrupted cortical E-I synaptic balance.

synapsesocial.com/papers/6a8c1213039371f2a3898012 https://doi.org/10.1161/jaha.124.035080

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Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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