Erebosis of Neurons May Exist in the Brain with Alzheimer’s Disease

Erebosis is a newly described form of cell death but has been reported only in the gut enterocytes of <i>Drosophila</i>, a group of fast turnover cells. Angiotensin-converting enzyme 2 (ACE2) accumulation in cells is a biomarker for erebotic cells. Brain cell loss is a characteristic of patients with Alzheimer's disease (AD), the leading neurodegenerative disease. The objectives of this study are to determine whether there is erebosis in the mammalian brain. Here we show that there is more ACE2 staining in the hippocampus of old wild-type (C57BL/6J) male mice, female mice with AD neuropathology (3xTg-AD mice), and human AD sufferers. Some ACE2 positive cells have fragmented or small nuclei, lose NeuN staining and are positive for TUNEL staining, indicators for cell injury/dying. ACE2 positive cells are neurons in the hippocampus and are often positive for phospho-tau in the mice with AD neuropathology. Phospho-tau injected into the hippocampus of wild-type young adult mice increases its ACE2 expression. Some ACE2 staining is extracellular. Our results suggest that erebosis may exist in the mammalian brain and may be increased with aging and AD neuropathology. This form of death may occur in the long-lasting cells like neurons and can be activated by phospho-tau in the brain. Our findings highlight the therapeutic potential of regulating erebosis for attenuating brain aging and AD neuropathology.