TY - JOUR
T1 - Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits
AU - Tamayev, Robert
AU - Matsuda, Shuji
AU - Fà, Mauro
AU - Arancio, Ottavio
AU - D'Adamio, Luciano
PY - 2010/11/30
Y1 - 2010/11/30
N2 - According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease andfamilial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDDKI/+) genetically congruous with human cases. FDDKI/+ mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2+/- mice exhibit synaptic and memory deficits similar to FDDKI/+ mice, and memory loss of FDDKI/+ mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.
AB - According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease andfamilial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDDKI/+) genetically congruous with human cases. FDDKI/+ mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2+/- mice exhibit synaptic and memory deficits similar to FDDKI/+ mice, and memory loss of FDDKI/+ mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy.
KW - Amyloid-β precursor protein
KW - ITM2b
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UR - http://www.scopus.com/inward/citedby.url?scp=78049506839&partnerID=8YFLogxK
U2 - 10.1073/pnas.1011689107
DO - 10.1073/pnas.1011689107
M3 - Article
C2 - 21098268
AN - SCOPUS:78049506839
SN - 0027-8424
VL - 107
SP - 20822
EP - 20827
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 48
ER -