title: Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein.
abstract: Mutations in the beta-amyloid precursor protein are strongly associated with some cases of familial Alzheimer's disease. The normal physiological role of beta-amyloid precursor protein in the brain was evaluated in a cross-sectional analysis of mice deficient in beta-amyloid precursor protein. Compared with wild-type control mice the beta-amyloid precursor protein-null mice developed age-dependent deficits in cognitive function and also had impairments in long-term potentiation. In addition, the brains of the beta-amyloid precursor protein-null mice had marked reactive gliosis in many areas, especially in the cortex and hippocampus. A subpopulation of mice (n = 15) died prematurely (between three and 18 months of age). Analysis of another six mice from the same population that were showing weight loss and hypolocomotor activity exhibited a marked reactive gliosis as detected by immunoreactivity for glial fibrillary acidic protein and a profound loss of immunoreactivities for the presynaptic terminal vesicle marker proteins synaptophysin and synapsin and the dendritic marker microtubule-associated protein-2 in many brain areas, but most predominantly in the cortex and hippocampus. These results suggest that normal beta-amyloid precursor protein may serve an essential role in the maintenance of synaptic function during ageing. A compromise of this function of the beta-amyloid precursor protein may contribute to the progression of the memory decline and the neurodegenerative changes seen in Alzheimer's disease.
authors: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
authors: G R
authors: GR
authors: Dawson
authors: G R
authors: GR
authors: Seabrook
authors: H
authors: H
authors: Zheng
authors: D W
authors: DW
authors: Smith
authors: S
authors: S
authors: Graham
authors: G
authors: G
authors: O'Dowd
authors: B J
authors: BJ
authors: Bowery
authors: S
authors: S
authors: Boyce
authors: M E
authors: ME
authors: Trumbauer
authors: H Y
authors: HY
authors: Chen
authors: L H
authors: LH
authors: Van der Ploeg
authors: D J
authors: DJ
authors: Sirinathsinghji
mesh_terms: D000375:Aging / Q000523:psychology*; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001362:Avoidance Learning; D015415:Biomarkers; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005911:Gliosis / Q000235:genetics*; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency*; D017661:Receptors, Presynaptic / Q000737:chemistry*; D016704:Synapsins / Q000172:deficiency*; D016708:Synaptophysin / Q000172:deficiency*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D017661:Receptors, Presynaptic; D016704:Synapsins; D016708:Synaptophysin