ABSTRACT
Alzheimer's disease is characterised by the accumulation of amyloid-beta peptide, which is cleaved from the copper-binding amyloid-beta precursor protein. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for amyloid-beta precursor protein and amyloid-beta in copper homeostasis. Amyloid-beta precursor protein is a member of a multigene family, including amyloid precursor-like proteins-1 and -2. The copper-binding domain is similar among amyloid-beta precursor protein family members, suggesting an overall conservation in its function or activity. Here, we demonstrate that double knockout of amyloid-beta precursor protein and amyloid precursor-like protein-2 expression results in significant increases in copper accumulation in mouse primary cortical neurons and embryonic fibroblasts. In contrast, over-expression of amyloid-beta precursor protein in transgenic mice results in significantly reduced copper levels in primary cortical neurons. These findings provide cellular neuronal evidence for the role of amyloid-beta precursor protein in copper homeostasis and support the existing hypothesis that amyloid-beta precursor protein and amyloid precursor-like protein-2 are copper-binding proteins with functionally interchangeable roles in copper homeostasis.
Subject(s)
Amyloid beta-Protein Precursor/physiology , Copper/metabolism , Fibroblasts/metabolism , Neurons/metabolism , Amyloid beta-Protein Precursor/deficiency , Amyloid beta-Protein Precursor/genetics , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Copper Radioisotopes , Disease Models, Animal , Fibroblasts/cytology , Gene Expression , Homeostasis/genetics , Mice , Mice, Knockout , Mice, Transgenic , Neurons/cytologyABSTRACT
The cellular origin of the acetylcholinesterase (AChE) associated with amyloid plaques in the Alzheimer's disease (AD) brain is unknown. In this study we report that amyloid beta-peptides (Abeta) increased AChE levels in both neuronal and astrocytic primary cultures, supporting the possibility that both neurons and glia may make a direct contribution to the pool of AChE seen around amyloid deposits in the AD brain.
Subject(s)
Acetylcholinesterase/biosynthesis , Amyloid beta-Peptides/pharmacology , Astrocytes/drug effects , Neurons/drug effects , Peptide Fragments/pharmacology , Animals , Astrocytes/enzymology , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Embryo, Mammalian , Mice , Mice, Inbred C57BL , Neurons/enzymologyABSTRACT
There is increasing evidence for disturbances in nicotinic acetylcholine receptor (nAChR) function in Alzheimer's disease (AD). nAChRs are involved in the regulation of many processes, including synaptic plasticity and memory. Levels of nAChRs are altered in the Alzheimer brain and there is evidence that the amyloid betaprotein (Abeta) can directly bind to nAChRs. Nicotinic agonists may also protect cells from Abeta toxicity. Drugs which interact with the nAChR or which inhibit Abeta binding to nAChRs may be of value for the treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Brain/metabolism , Cholinergic Fibers/metabolism , Neuronal Plasticity/physiology , Receptors, Neurotransmitter/metabolism , Alcohol Oxidoreductases , Amyloid beta-Peptides/metabolism , DNA-Binding Proteins/metabolism , Humans , Long-Term Potentiation , Phosphoproteins/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolismABSTRACT
Previous studies have shown that a minor glycoform of acetylcholinesterase (AChE) is increased in Alzheimer's disease brain and cerebrospinal fluid. This glycoform can be distinguished from other AChE species by its lack of binding to concanavalin A (Con A). In this study, the temporal relationship between AChE glycosylation and Abeta deposition was examined in Tg2576 mice. There was a significant (p < 0.05) difference in AChE glycosylation in Tg2576 mice compared with age-matched background strain control mice at 4 months of age. This difference in glycosylation was also observed in 8- and 12-month-old Tg2576 mice. In contrast, Abeta plaques were only seen in the Tg2576 mice at 12 months of age, and were not detected at 4 and 8 months of age. Soluble human-sequence Abeta was detected as early as 4 months of age in the transgenic mice. The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid. The results demonstrate that in transgenic mice altered AChE glycosylation is associated with very early events in the development of AD-like pathology. The study supports the possibility that glycosylation may also be a useful biomarker of AD.
