Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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) activation in the brain is implicated early in the pathogenesis of Alzheimer disease (AD). In view of the need for early AD diagnosis, brain Casp6 activity was investigated by measuring Tau cleaved by Casp6 (TauΔCasp6) protein in postmortem cerebrospinal fluid (CSF) of 7 non-cognitively impaired, 5 mild cognitively impaired and 12 mild, moderate and severe AD patients. Levels of TauΔCasp6 in CSF accurately reflected the levels of active Casp6 and TauΔCasp6 detected using immunohistochemistry in hippocampal sections from the same individuals. Levels of CSF TauΔCasp6 significantly correlated with AD severity, and with lower global cognitive scores, mini mental state exam, and episodic, semantic, and working memory scores. Regression analyses suggested that the CSF TauΔCasp6 levels combined with TauΔCasp6 brain pathology predict cognitive performance. These results indicate that CSF TauΔCasp6 levels holds promise as a novel early biomarker of AD.