Increased Caspase-6 activity in the human anterior olfactory nuclei of the olfactory bulb is associated with cognitive impairment

Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating. To examine this possibility, we examined the presence of Casp6 activity, neurofibrillary tangle formation and amyloid deposition by immunohistochemistry with neoepitope antisera against the p20 subunit of active Casp6 and Tau cleaved by Casp6 (Tau∆Casp6), phosphorylated Tau paired helical filament (PHF-1) antibodies and anti-β-amyloid antiserum, respectively, in brains from individuals with no or mild cognitive impairment and Alzheimer disease (AD) dementia. Co-localization of Casp6 activity, PHF-1 and β-amyloid was detected mostly in the anterior olfactory nucleus (AON) of the olfactory bulb. The levels of active Casp6 in the AON, which were the highest in the AD brains, correlated with PHF-1 levels, but not with β-amyloid levels. AON Tau∆Casp6 levels correlated with entorhinal cortex Casp6 activity and PHF-1 levels. Multiple regression analyses demonstrated that AON Casp6 activity was associated with lower global cognitive function, mini mental state exam, episodic memory and semantic memory scores. These results suggest that AON Casp6 activity could lead to Casp6-mediated degeneration in the entorhinal cortex, but cannot exclude the possibilities that entorhinal cortex degeneration signals degeneration in the AON or that the pathologies occur in both regions independently. Nevertheless, AON Casp6 activity reflects that of the entorhinal cortex.