Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.
Highlights
Alzheimer’s disease (AD) is an ever-growing neurological disorder, with numbers projected to attain 14 million by 2050 [1]
In order to attain a clear picture of the effects of caspase-6 KO on 5xFAD mice, both males and females were tested separately
In the 5xFAD mouse model, a drastic phenotype is observed in aging females, leading to decreased motor behavior and sometimes paralysis and death [42]
Summary
Alzheimer’s disease (AD) is an ever-growing neurological disorder, with numbers projected to attain 14 million by 2050 [1]. It is considered one of the leading causes of death in America, and tremendous amounts of money have been spent to combat the disorder to no avail. Amyloid precursor protein (APP) is an internal membrane protein that can be cleaved by several enzymes. The amyloid-β (Aβ) peptide is generated by the proteolytic cleavage of APP by β- and γ-secretases [2]. The β-cleaved peptide can be aberrantly folded and conform into amyloid oligomers and plaques, which are thought to be an early event in the progression of AD [3]. The APP can be cleaved at APP/C99 by caspases which, in turn, produces a neurotoxic peptide (C31) [4]
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