Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

Robert Tamayev, Shuji Matsuda, Mauro Fà, Ottavio Arancio, Luciano D'Adamio

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20822-20827
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number48
DOIs
StatePublished - Nov 30 2010

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Neuronal Plasticity
Memory Disorders
Amyloid
Dementia
Tauopathies
Amyloid Plaques
Amyloidosis
Alzheimer Disease

Keywords

  • Amyloid-β precursor protein
  • ITM2b

ASJC Scopus subject areas

  • General

Cite this

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits. / Tamayev, Robert; Matsuda, Shuji; Fà, Mauro; Arancio, Ottavio; D'Adamio, Luciano.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 48, 30.11.2010, p. 20822-20827.

Research output: Contribution to journalArticle

Tamayev, Robert ; Matsuda, Shuji ; Fà, Mauro ; Arancio, Ottavio ; D'Adamio, Luciano. / Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 48. pp. 20822-20827.
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