Overexpression of HIF-2α in Alzheimer's disease Resilient Patients

Alzheimers disease (AD) Resilient individuals are characterized by having a degree of amyloid plaques at level with that of demented individuals, but a reduced amount of abnormal neurofibrillary protein "tangles" (NFTs). NFTs, also known to be upregulated under hypoxic conditions, become clinically relevant when involved in the stratum radiatum. In this paper, we show this region and more to have significant increases of hypoxic adaptive protein, HIF-2, within AD resilient cases. Pericyte staining was present in the stratum lacunosum and radiatum of all cases affected by AD pathology (n = 4) but in AD resilient cases were increased by 12-fold (n=3) p<.0001. No staining was detected in normal cases (n=2). HIF-2 was also only present in hippocampal neuronal nuclei of AD resilient cases, including the dentate gyrus and CA1. Cytoplasmic staining of pyramidal neurons within the subiculum was seen in all cases affected by AD pathology. The intensity of HIF-2 appears to be specific to known regions of protection in AD resilience and to increase on a gradient that corresponds to protection against dementia. These results also highlight the stratum lacunosum and radiatum as regions critically impacted by hypoxic insult among AD cases. SignificanceHIF-2 directly regulates expression of erythropoietin (EPO), a neuroprotective glycoprotein that in brain pericytes is completely dependent upon activation of HIF-2. To date, only indirect evidence exists that shows that brain pericyte-derived EPO can reach the bloodstream via HIF-2 expression (Urrutia et al, 2016). In this study, we provide novel preliminary findings that directly show HIF-2 expression in pericytes of human brains. Additionally, its localization is specific to the CA1 of the hippocampus, a region critical for hypoxic adaptation and the progression of Alzheimers disease. Finally, we present evidence of neuronal expression of HIF-2 in other critical regions of protection within AD resilient cases.