title: Neurobiological elements of cognitive dysfunction in down syndrome: exploring the role of APP.
abstract: Down syndrome (DS) is the most common cause of cognitive dysfunction in children. Additionally, most adults with DS will eventually show both clinical and neuropathologic hallmarks of Alzheimer's disease (AD). The hippocampal formation constitutes the primary target for degeneration in both AD and DS. Over the past few years, we have studied the molecular mechanisms behind degeneration of this region and its major inputs in mouse models of DS. Our investigation has suggested that the loss of hippocampal inputs, particularly cholinergic and noradrenergic terminals, leads to de-afferentation of this region in the Ts65Dn mouse model of DS. Interestingly, we were able to link the overexpression of amyloid precursor protein (App) gene to degeneration of cholinergic and noradrenergic neurons in DS mouse models. We examined the underlying mechanisms of degeneration of multiple systems with extensive projections to the hippocampus in DS and its mouse models and the role of App overexpression in neurodegeneration. Understanding mechanisms behind hippocampal dysfunction has helped us to test several therapeutic strategies successfully in mouse models of DS. Here we review these strategies and mechanisms and discuss ways to translate our findings into possible interventions in humans.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Millan Sanchez
authors.forename: Sietske N
authors.initials: SN
authors.lastname: Heyn
authors.forename: Devsmita
authors.initials: D
authors.lastname: Das
authors.forename: Sarah
authors.initials: S
authors.lastname: Moghadam
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Martin
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salehi
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D059329:Cholinergic Neurons / Q000378:metabolism / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D006801:Humans
chemical_list: D016564:Amyloid beta-Protein Precursor