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

Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20822-7. doi: 10.1073/pnas.1011689107. Epub 2010 Nov 22.

Abstract

According to the prevailing "amyloid cascade hypothesis," genetic dementias such as Alzheimer's disease and familial 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 (FDD(KI/+)) genetically congruous with human cases. FDD(KI/+) 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 FDD(KI/+) mice, and memory loss of FDD(KI/+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amyloid / metabolism*
  • Amyloidosis / complications
  • Amyloidosis / pathology
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Cataract / complications
  • Cataract / pathology
  • Cataract / physiopathology
  • Cerebellar Ataxia / complications
  • Cerebellar Ataxia / pathology
  • Cerebellar Ataxia / physiopathology
  • Deafness / complications
  • Deafness / pathology
  • Deafness / physiopathology
  • Dementia / complications
  • Dementia / pathology
  • Dementia / physiopathology
  • HeLa Cells
  • Humans
  • Long-Term Potentiation / physiology
  • Membrane Glycoproteins
  • Membrane Proteins / genetics
  • Memory Disorders / complications*
  • Memory Disorders / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neuronal Plasticity / physiology*
  • Signal Transduction*
  • Synapses / metabolism
  • Synapses / pathology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid
  • ITM2B protein, human
  • Itm2b protein, mouse
  • Membrane Glycoproteins
  • Membrane Proteins

Supplementary concepts

  • Dementia, familial Danish