Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

LeBlanc, Andréa C.; Ramcharitar, Jasmine; Afonso, Veronica M.; Hamel, Édith; Bennett, David A.; Pakavathkumar, Prateep; Albrecht, Steffen

doi:10.1038/cdd.2013.194

Cited by 47 publications

(77 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging [157]. The activation of caspase-6 in mouse CA1 neurons is a sufficient event to induce neuronal degeneration and age-dependent memory impairment, suggesting that lower cognitive performance of aged humans could be related to caspase-6 and targeting caspase-6 could be a potential treatment strategy for AD [158]. In addition, knockdown of Nfr2 resulted in reduced proteasome activity and resistance to stress and longevity, whereas its prolonged overexpression resulted in reduced longevity, indicating that proteostasis can be fundamental to accelerated brain aging [159].…”

Section: Neuronal Impairment In Agingmentioning

confidence: 99%

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

2015

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".

show abstract

Section: Neuronal Impairment In Agingmentioning

confidence: 99%

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

2015

View full text Add to dashboard Cite

show abstract

“…In aged humans, higher levels of Casp6 activity in the entorhinal cortex (ERC) and Cornus Ammonis 1 (CA1) regions of the hippocampus predict lower performance in episodic memory, the first type of memory to be decreased in AD [3, 47]. Post-natal expression of a self-activated form of human Casp6 in the hippocampal CA1 region of mouse brains induces age-related spatial and episodic memory impairment and is associated with early inflammation and neuronal loss [39]. Unlike the other two effector caspases, Casp3 and Casp7, Casp6 does not induce cell death when activated [26, 33].…”

Section: Introductionmentioning

confidence: 99%

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

Foveau

Albrecht

Bennett

et al. 2016

acta neuropathol commun

View full text Add to dashboard Cite

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.

show abstract

“…Thus, this work demonstrates the usefulness of 291 proteomics in linking the function of particular brain regions to the 292 underlying protein expression profile. Moreover, LeBlanc and col-293 leagues recently reported that the pro-apoptotic Caspase-6 is highly 294 expressed in the CA1 region of aged human hippocampus with 295 cognitive impairment[31], which highlights the capability of prote-296 omics to identify disease processes.297 Further elucidating the ability of proteomics to link functional anat-298 omy to protein expression, differential expression of proteins in hippo-299 campal subregions has been noted. For instance, proteins enriched in 300 the DG region include two well-established disease associated proteins: 301 disrupted in schizophrenia 1 protein (DISC1) and nuclear receptor 302 subfamily 2 group E member 1 (NR2E1).…”

mentioning

confidence: 97%

Proteogenomics of the human hippocampus: The road ahead

Kang

Byun

Kim

et al. 2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Cited by 47 publications

References 45 publications

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

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

Proteogenomics of the human hippocampus: The road ahead

Contact Info

Product

Resources

About