Targeting HIF-P4H-2 in APP/PS1 Alzheimer's mouse model improves glucose metabolism, reduces dystrophic neuritis, and maintains exploratory activity.

Alzheimer's disease is the most common cause of dementia with limited treatment options. We asked whether activation of the hypoxia-inducible factor (HIF) pathway via genetic deficiency of HIF prolyl 4-hydoxylase-2 (HIF-P4H-2; also known as PHD2/EGLN1) could be an Alzheimer's disease-modifying therapy using transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) female mice. At 12 months of age, APP/PS1/Hif-p4h-2(gt/gt) mice had 20% less cortical amyloid-β (Aβ) and less dystrophic neurites around amyloid plaques compared with APP/PS1 mice used as controls. Compared with controls, APP/PS1/Hif-p4h-2(gt/gt) mice were leaner, had better glucose tolerance and insulin sensitivity, and higher expression levels of an HIF target, glucose transporter 1, in the brain. These changes associated with lesser Aβ toxicity in APP/PS1/Hif-p4h-2(gt/gt) mice linking indices of neurodegeneration with HIF-P4H-2 deficiency-mediated amelioration on brain and systemic glucose metabolism. In open field and dark-light tests, APP/PS1/Hif-p4h-2(gt/gt) mice maintained their behavior during aging, whereas controls showed a change by 60% to 80% in exploratory activity and anxiety parameters from 6 to 12 months. Maintenance of behavior associated with cortical Hif-p4h-2 mRNA downregulation, lesser Aβ toxicity, and lower white adipose tissue inflammation in APP/PS1/Hif-p4h-2(gt/gt) mice. Altogether, these data connect activation of the HIF pathway via HIF-P4H-2 deficiency to neuroprotection in the APP/PS1 Alzheimer's mouse model.