Dataset Information

?- but not ?-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

ABSTRACT: A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-? precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by ?-secretase rescues synaptic/memory deficits in a mouse model of FDD. ?-cleavage of APP yields amino-terminal-soluble APP? (sAPP?) and ?-carboxyl-terminal fragments (?-CTF). Processing of ?-CTF by ?-secretase releases amyloid-? (A?), which is assumed to cause AD. However, inhibition of ?-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPP? and/or ?-CTF, rather than A?, are the toxic species causing dementia, and indicate that reducing ?-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-A? therapies in humans advise against targeting ?-secretase cleavage of APP and/or A?.

SUBMITTER: Tamayev R

PROVIDER: S-EPMC3376850 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

Tamayev Robert R Matsuda Shuji S Arancio Ottavio O D'Adamio Luciano L D'Adamio Luciano L

EMBO molecular medicine 20120123 3

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by ...[more]

PMID: 22170863

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Project description:Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related ?-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate ?-synuclein (?S) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how ?S abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer's disease. Previously, we found that familial Parkinson's disease-linked human mutant A53T ?S causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of ?-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau-/-), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting ?S expression or accumulation of selected toxic ?S oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau-/- mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T ?S-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in ?-synucleinopathies.

Dataset Information

?- but not ?-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

Publications

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

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