Abstract
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.
Highlights
Identification of specific early molecular mechanisms underlying neurodegeneration and leading to age-related cognitive impairment and Alzheimer disease (AD) dementia may provide novel therapeutic targets against which efficient therapies can be developed
The anterior olfactory nucleus (AON) is the region of the olfactory bulb most immunopositive to active Casp6, TauΔCasp6, Paired helical filament (PHF-1) Tau and Aβ The AON area of the olfactory bulb whose neurites extend to the entorhinal cortex (ERC) (Fig. 1a) was chosen for quantification of Casp6 activity since the AON represents the area that is most strongly immunopositive to the neoepitope antisera against the p20 active subunit of Casp6 and TauΔCasp6, phosphorylated Tau PHF-1 antibodies and anti-Aβ antiserum (Fig. 1b & c)
TauΔCasp6 immunoreactivity was detected in neurofibrillary tangles (NFT)-containing neurons and neuropil threads of adjacent tissue sections, and was more abundant than the immunoreactivity of Levels of active Casp6 correlate with TauΔCasp6 and PHF-1, but not with Aβ, in the AON of the olfactory bulb Spearman’s correlation showed a strong positive relationship between the anti-active Casp6 and the TauΔCasp6 in the AON of the olfactory bulb (Fig. 2a)
Summary
Identification of specific early molecular mechanisms underlying neurodegeneration and leading to age-related cognitive impairment and AD dementia may provide novel therapeutic targets against which efficient therapies can be developed. Post-natal expression of a self-activated form of human Casp in the hippocampal CA1 region of mouse brains induces agerelated spatial and episodic memory impairment and is associated with early inflammation and neuronal loss [39]. In human primary neurons transfected to overexpress wild type or Swedish and London mutant amyloid precursor protein (APP), three conditions associated with familial AD [11, 48], Casp is activated in the absence of Casp activity and causes axonal degeneration [37, 55]. This is consistent with the absence of significant amounts of either active Casp or Casp in AD brains that exhibit high amounts of active Casp6 [37, 50, 57]
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