Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice.
Increasing evidence points to synaptic plasticity impairment as one of the first events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in different transgenic AD models that overexpress familial AD mutant forms of amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting results. Both long-term potentiation (LTP) and basal synaptic transmission (BST) have been found to be both unchanged and altered in different models and under differing experimental conditions. Because of their more robust amyloid-beta (Abeta) deposition, double transgenic mice currently are used by several laboratories as an AD model. Here, we report that mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of age. Interestingly, reduced LTP paralleled plaque appearance and increased Abeta levels and abnormal short-term memory (working memory). BST and long-term memory (reference memory) are impaired only later (approximately 6 months) as amyloid burden increases. Abeta pathology across different ages did not correlate with synaptic and cognitive deficits, suggesting that Abeta levels are not a marker of memory decline. In contrast, progression of LTP impairment correlated with the deterioration of working memory, suggesting that percentage of potentiation might be an indicator of the cognitive decline and disease progression in the APP/PS1 mice.
Trinchese
Fabrizio
F
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
Liu
Shumin
S
Battaglia
Fortunato
F
Walter
Sean
S
Mathews
Paul M
PM
Arancio
Ottavio
O
D000367:Age Factors; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000097:blood; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology / Q000528:radiation effects; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology / Q000528:radiation effects; D008565:Membrane Proteins / Q000235:genetics; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis / Q000097:blood; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C402222:MTCH1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)