Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein

• Published in: Neuroscience 1999-01, Vol.90 (1), p.1-13
• Main Authors: Dawson, G.R, Seabrook, G.R, Zheng, H, Smith, D.W, Graham, S, O'Dowd, G, Bowery, B.J, Boyce, S, Trumbauer, M.E, Chen, H.Y, Van der Ploeg, L.H.T, Sirinathsinghji, D.J.S
• Format: Article
• Language: English
• Subjects: Aging - psychology; Alzheimer Disease - metabolism; Amyloid beta-Protein Precursor - deficiency; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - physiology; Animals; Avoidance Learning; Biological and medical sciences; Biomarkers; Cerebral Cortex - chemistry; Cerebral Cortex - pathology; cognition; Cognition Disorders - genetics; Development. Senescence. Regeneration. Transplantation; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; gene deletion; Glial Fibrillary Acidic Protein - analysis; gliosis; Gliosis - genetics; Hippocampus - chemistry; Hippocampus - pathology; long term potentiation; Long-Term Potentiation - genetics; Male; Maze Learning; Mice; Mice, Knockout; Microtubule-Associated Proteins - deficiency; mouse; Receptors, Presynaptic - chemistry; Synapsins - deficiency; synaptic function; Synaptophysin - deficiency; Vertebrates: nervous system and sense organs; β-amyloid precursor protein
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00410-2

Mutations in the β-amyloid precursor protein are strongly associated with some cases of familial Alzheimer's disease. The normal physiological role of β-amyloid precursor protein in the brain was evaluated in a longitudinal analysis of mice deficient in β-amyloid precursor protein. Compared with wild-type control mice the β-amyloid precursor protein-null mice develop age-dependent deficits in cognitive function and also have impairments in long-term potentiation. In addition, the brains of the β-amyloid precursor protein-null mice have marked reactive gliosis in many areas especially in the cortex and hippocampus. A sub-population 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 β-amyloid precursor protein may serve an essential role in the maintenance of synaptic function during ageing. A compromise of this function of the β-amyloid precursor protein may contribute to the progression of the memory decline and the neurodegenerative changes seen in Alzheimer's Disease.