New Cortical Neurodegenerative Pathways in the Hypertensive Rat Brain

Hypertension is a risk factor for neurodegenerative diseases. We hypothesized that chronic hypertension underlies neurodegeneration. In this study, we examined the expression of brain cortical proteins involved in homeostasis, apoptosis, and brain functions in Spontaneously Hypertensive Rats (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. We used paraffin-embedded brain sections of 8-month-old SHR and WKY rats, immunohistochemically stained and analyzed by image processing. In SHR, cytochrome c oxidase subunit 7A increased, indicative of hypoxia; heat shock protein 40, the chaperon for refolding proteins, decreased, leading to accumulation of misfolded proteins; the levels of both voltage-gated sodium channels, Na1.2, 1.6, decreased, reflecting attenuation of the action potential, causing axonal injury; autophagy-related protein 4A (Atg4a), an essential protein of autophagy, decreased, reducing the removal of misfolded proteins; demyelination, the hallmark of neurodegeneration, was shown; modulation of both histone deacetylases 2 and histone acetyltransferase 1 was shown, indicative of altered regulation of gene transcription; increased activated (cleaved) caspase-3, indicative of apoptosis. These new findings suggest that chronic hypertension induces hypoxia and oxidative stress, axonal injury, accelerates the accumulation of misfolded proteins and apoptosis, pathways preceding neurodegeneration.