Caspase-6 (Casp6), a cysteinyl protease that induces axonal degeneration, is activated early in Alzheimer Disease (AD) brains. To determine whether Casp6 activation is responsible for early cognitive impairment, we investigated the abundance of Casp6 activity, paired helical filament–1 (PHF-1) phosphorylated Tau and amyloid beta peptide (Aβ) pathology by immunohistochemistry in the hippocampal formation of aged non–cognitively impaired (NCI) individuals. Casp6 activity was restricted to the entorhinal cortex (ERC) and CA1 regions of the hippocampus. Pathology scores were then correlated with cognitive scores obtained within 1 year of death. Regression analyses revealed that ERC and CA1 Casp6 activity were the main contributor to lower episodic memory performance, whereas ERC PHF-1 pathology predicted lower semantic and working memory performance. Aβ did not correlate with any of the cognitive tests. Because Casp6 activity and PHF-1 pathology are intimately associated with AD pathology and memory decline is an early event in AD, we conclude that Casp6 activity and PHF-1 immunoreactivity in ERC identifies aged individuals at risk for developing AD.
Caspase-6 (Casp6) activity is present in neurofibrillary tangles (NFT), neuropil threads (NPT), and neuritic plaques (NP) of sporadic Alzheimer’s disease (AD) brains and in familial AD caused by amyloid precursor protein (APP), presenilin I, or presenilin II mutations (Albrecht et al., 2009, Albrecht et al., 2007). Previously, we have shown that Casp6 activity occurs at all stages of AD and is equally abundant and distributed in mild, moderate, severe, and very severe forms of AD (Albrecht et al., 2007). Surprisingly, Casp6 activity was detected in some non–cognitively impaired (NCI) brains, and the levels of Casp6 activity correlated inversely with cognitive scores measured within a year of death. However, although Casp6 activity was quite abundant in the hippocampal formation and in the cortices of AD brains, high levels of Casp6 activity in NCI brains were mostly limited to the entorhinal cortex (ERC), the first area to be affected pathologically by AD according to Braak staging (Braak and Braak, 1995, Lace et al., 2009).
Casp6, is involved in inflammation and apoptosis, does not induce cell death when activated in AD neurons or in mammalian cell lines (Gray et al., 2010, Guo et al., 2004, Klaiman et al., 2009), but induces axonal degeneration in primary cortical human neurons and commissural and sympathetic mouse neurons (Klaiman et al., 2008, Nikolaev et al., 2009, Sivananthan et al., 2010). Casp6 cleaves several cytoskeletal (alpha-tubulin, Tau) or cytoskeletal-regulating proteins including post-synaptic actin regulating proteins, Drebrin, Spinophilin, actinin-1, and actinin-4 (Klaiman et al., 2008). In addition, Casp6 activation increases the production of the amyloid beta peptide (Aβ) (LeBlanc, 1995); however, the effect is not through direct cleavage of APP as originally thought (Gervais et al., 1999, Pellegrini et al., 1999, Weidemann et al., 1999) but rather occurs by caspase-dependent cleavage of an inhibitor of the beta secretase (Tesco et al., 2007, Tesco et al., 2003). Furthermore, Casp6 cleaves valosin-containing protein and impairs its ability to target misfolded and ubiquitinated proteins to the proteasome for degradation (Halawani et al., 2010). Together, these studies indicate that Casp6 activity affects a number of parallel degenerative pathways that are likely to impair neuronal function.
To determine the impact of Casp6 activity on the cognitive performance of NCI individuals compared to accepted AD pathological markers, we analyzed the extent of active Casp6, amyloid beta peptide (Aβ), and PHF-1 immunopositive pathology in different areas of the hippocampal formation of 17 NCI individuals and correlated these pathological scores with cognitive scores obtained within a year of death
