Amyloid-beta peptide and phosphorylated tau in the frontopolar cerebral cortex and in the cerebellum of toothed whales: aging vs hypoxia

Abstract

Background: Alzheimer’s disease results from the interplay of multiple risk factors and their effects. Diving mammals may be routinely exposed to severe hypoxia when submerged. Among toothed whales, the beaked whales are particularly cryptic and routinely dive deeper than 1,000 m for about one hour in order to hunt deep-water squid and fish. We hypothesized that hypoxia could be a possible risk factor for neurodegenerative alterations in the central nervous system of beaked whales in particular, and toothed whales in general. Results: Samples of frontal cerebral cortex and cerebellum were collected from nine animals, representing six different species of the suborder Odontoceti. Immunohistochemical analysis employed a monoclonal anti-β-amyloid (Aβ) and a polyclonal anti-neurofibrillary tangle (NFT) antibodies. Six of nine (67%) animals showed positive immunolabeling for Aβ and/or NFT. The most striking findings were intranuclear Aβ immunopositivity in cerebral cortical neurons and NFT immunopositivity in cerebellar Purkinje neurons with granulovacuolar degeneration. Herein, we present immunohistopathological findings classic of Alzheimer’s and other neurodegenerative diseases in humans, in different brain locales of odontocete cetaceans. This study represents the first description of Aβ and NFT in the brain of beaked whales, adding also to the non-existent descriptions of GVD in the brain of non-experimental animals, being specifically the first report of granulovacuolar degeneration in the cerebellum. Our results further confirm the rarely reported intranuclear expression of Aβ. Conclusions: These findings could be linked to hypoxic phenomena, as they were more extensive in the brains of beaked whales, and not only in aged individuals. Therefore, a novel hypothesis linking hypoxia and neurodegeneration microscopic hallmarks in cetaceans is proposed. Despite their adaptations, diving mammals could be vulnerable to sustained and repetitive brain hypoxia. Future comparative pathological and neuroprotective investigations may prove of great value to Alzheimer’s disease and other neurodegenerative diseases in humans.