. Influence of the amyloid precursor protein locus on dementia in Down syndrome. Neurology. 2004 Jun 8;62(11):1996-8. PubMed.


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  1. The gene for APP is on chromosome 21, which is triplicated in Down syndrome (DS). While overexpression of APP in DS brain has been shown, and while it is commonly assumed that gene dosage specifically for APP causes the dementia that DS individuals develop late in life, no lab has ever proved directly that APP, rather than the 100+ other genes on chromosome 21, causes DS dementia. In this paper, the authors show that polymorphic variation in the APP gene influences the age of onset of dementia in DS individuals. This manuscript is, to my knowledge, the first direct evidence that the APP locus is indeed involved causally in DS dementia.

  2. I agree with Rachael Neve that this is an interesting report suggesting that APP is causally involved in Down's syndrome dementia.

    Of relevance to this story is a recent report by Anne Cataldo et al. demonstrating that APP gene dosage modulates an AD-relevant phenotype in a mouse model of DS. The Ts65Dn mouse is trisomic for the segment of mouse chromosome 16 homologous to human chromosome 21, which includes the murine APP gene. Ts65Dn mice display developmental delay, abnormal behaviors that are thought to be analogous to mental retardation, and degeneration of basal forebrain cholinergic neurons.

    Cataldo and colleagues showed that neurons in the Ts65Dn mouse showed pathological alterations in early endocytic compartments that are similar to those seen in preclinical AD and human juvenile DS. She and her colleagues have documented over the last five years or so that these changes in neuronal early endosomes are a very early event during AD pathogenesis and an invariant feature of DS. When Ts65Dn mice were crossed to an APP knockout mouse (restoring APP to diploid yet leaving the remaining genes in this region triploid) the endosomal pathology disappeared. From the Cataldo paper it is not yet known whether restoration of APP to diploid in the Ts65Dn mouse rescues the neurodegenerative phenotype, but given this report by Margallo-Lana linking APP to the age of onset of dementia in human DS this would be an interesting question to address.


    . App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci. 2003 Jul 30;23(17):6788-92. PubMed.

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