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. 2021 Feb 22;2(2):zqab010.
doi: 10.1093/function/zqab010. eCollection 2021.

PIP2 Improves Cerebral Blood Flow in a Mouse Model of Alzheimer's Disease

Amreen Mughal  1 , Osama F Harraz  1   2 , Albert L Gonzales  1   3 , David Hill-Eubanks  1 , Mark T Nelson  1   2   4
Affiliations

PIP2 Improves Cerebral Blood Flow in a Mouse Model of Alzheimer's Disease

Amreen Mughal et al. Function (Oxf). .

Abstract

Alzheimer's disease (AD) is a leading cause of dementia and a substantial healthcare burden. Despite this, few treatment options are available for controlling AD symptoms. Notably, neuronal activity-dependent increases in cortical cerebral blood flow (CBF; functional hyperemia) are attenuated in AD patients, but the associated pathological mechanisms are not fully understood at the molecular level. A fundamental mechanism underlying functional hyperemia is activation of capillary endothelial inward-rectifying K+ (Kir2.1) channels by neuronally derived potassium (K+), which evokes a retrograde capillary-to-arteriole electrical signal that dilates upstream arterioles, increasing blood delivery to downstream active regions. Here, using a mouse model of familial AD (5xFAD), we tested whether this impairment in functional hyperemia is attributable to reduced activity of capillary Kir2.1 channels. In vivo CBF measurements revealed significant reductions in whisker stimulation (WS)-induced and K+-induced hyperemic responses in 5xFAD mice compared with age-matched controls. Notably, measurements of whole-cell currents in freshly isolated 5xFAD capillary endothelial cells showed that Kir2.1 current density was profoundly reduced, suggesting a defect in Kir2.1 function. Because Kir2.1 activity absolutely depends on binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the channel, we hypothesized that capillary Kir2.1 channel impairment could be corrected by exogenously supplying PIP2. As predicted, a PIP2 analog restored Kir2.1 current density to control levels. More importantly, systemic administration of PIP2 restored K+-induced CBF increases and WS-induced functional hyperemic responses in 5xFAD mice. Collectively, these data provide evidence that PIP2-mediated restoration of capillary endothelial Kir2.1 function improves neurovascular coupling and CBF in the setting of AD.

Keywords: Alzheimer’s disease; Kir2.1; PIP2; capillaries; cerebral blood flow; endothelial cells; functional hyperemia; neurovascular coupling; phosphoinositides; potassium channels.

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Graphical abstract
Figure 1.
Figure 1.
Functional Hyperemia is Impaired in 5xFAD Mice In vivo. Representative 3D in vivo images showing the vascular network (red) and β-amyloid plaques (yellow) accumulated in the cortex of (a) control and (b) 5xFAD mice. Block width = 425 × 425 μm; block depth = 300 μm (n = 3 mice each). (c) Representative traces (left) and summary data (right) showing WS-induced changes in CBF in control and 5xFAD mice (n = 5 mice each; **P < 0.01, ***P < 0.001, two-way ANOVA with Tukey’s test as post hoc analysis). (d) Representative line scans (1 s each) and summary data showing RBC flux responses to 10 mM K+ in control (baseline, 35 ± 4 cells/s; 10 mM K+, 60 ± 5 cells/s; n = 10 paired experiments, five mice) and 5xFAD mice (baseline, 27 ± 4 cells/s; 10 mM K+, 32 ± 4 cells/s; n = 10 paired experiments, five mice). **P < 0.01 (paired Student’s t-test).
Figure 2.
Figure 2.
PIP2 Restores Capillary Kir2.1 Channel Function and K+ Sensing in 5xFAD Capillaries. (a) Averaged traces of Kir2.1 current in brain cECs from control (black; n = 10 cECs from four mice) and 5xFAD (green; n = 14 cECs from four mice) mice, recorded in the conventional whole-cell configuration using voltage ramps from −140 to +40 mV. Light colors indicate SEM. (b) Representative traces of Kir2.1 current in two 5xFAD cECs in the absence (green) or presence (purple) of diC16-PIP2 in the bath solution, recorded using the same protocol as in Panel a. (c and d) Scatter-plot averages of inward current densities at −140 mV in 5xFAD (c) and control (d) cECs in the absence and presence of diC16-PIP2 in the bath solution. (n = 7–14 cECs/group, n = 6 mice for both control and 5xFAD groups; **P < 0.01; n.s., not significant; unpaired Student’s t-test). For PIP2 experiments, cECs were incubated with a bath solution supplemented with 10 µM diC16-PIP2 for ∼20 min prior to recordings. (e) Representative line scans and summary data showing RBC flux responses to 10 mM K+ in control (baseline, 31 ± 4 cells/s; 10 mM K+, 53 ± 8 cells/s; n = 10 paired experiments, five mice) and 5xFAD mice (baseline: 26 ± 5 cells/s; 10 mM K+, 49 ± 7 cells/s; n = 10 paired experiments, five mice) 20 min after the systemic injection of diC16-PIP2. *P < 0.05 (paired Student’s t-test). (f) Representative traces (left) and summary data (right) showing WS-induced changes in CBF in 5xFAD mice before (baseline) and after the consecutive administration of diC16-PIP2 (intravascular injection) and Ba2+ (cranial window application) (n = 5 mice; ****P < 0.0001; one-way repeated measures ANOVA with Tukey’s test for post hoc analysis).
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