Chronic hypoxia aggravates Alzheimer’s disease pathology by causing microglial dysfunction

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia. In many cases AD patients present concomitant vascular pathology. Low oxygen levels are also frequently found in the brain of AD patients. The most accepted hypothesis to explain the correlation between hypoxia and AD is the deposition of amyloid ß (Aß) occurring in the microvasculature (amyloid angiopathy) and the affectation by the disease of the locus coeruleus, a brain region involved in the control of brain blood flow. However, few data has been collected to understand the relation between hypoxia and AD progression. We show here the accumulation of the hypoxic marker HIF1 α (Hypoxia-inducible-factor 1α), the major transcription factor for the adaptation to hypoxic conditions, in the brain of AD patients by western blot. We have also characterized the consequences of chronic exposition to hypoxia in the progression of the disease using a widely accepted AD mice model. AD mice were exposed to physiologic hypoxia (8.5% oxygen, 21 days) at initial and advances stages of the pathology. Brains from hypoxic animals showed no differences in the Aß content and number of plaques, but they showed a clear reduction in the total number of microglial cells that was even more evident around the Aß plaques. In vitro analyses suggest that hypoxia slows down proliferation and chemotaxis towards polymeric Aß in both cell line and primary microglial cultures. Interestingly, the brain cortex from the hypoxic animals showed a high increase in the number of dystrophic neurites surrounding the microglia- free Aß plaques. We observed also a decrease in the mRNA levels of two markers of interneurons, Somatostatin and Neuropeptide-Y, in the hippocampus of hypoxic mice. These data suggest that hypoxia accelerates the progression of AD pathology. The pathway underlying microglial affectation by hypoxia has an enormous potential in neurodegenerative disorders where microglia function is correlated with the progression of the disease.