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Alzheimer’s disease, CaMKII, degeneration, locus coeruleus,
memory, noradrenaline, norepinephrine, pathogenesis
Abstract:
Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in
Alzheimer’s disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic
mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid toxicity and cognitive function, the
specific role of noradrenaline (NA) in AD is not well understood.
Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine -hydroxylase (DBH)
knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine -hydroxylase
(/) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal
long-term potentiation, and synaptic protein levels were assessed.
Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (/)
single mutant mice were augmented in DBH (/)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total
calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B
levels and were independent of amyloid accumulation. Spatial memory performance was partly improved by treatment with the NA
precursor drug L-threo-dihydroxyphenylserine.
Conclusions: These results indicate that early LC degeneration and subsequentNAdeficiency inADmay contribute to cognitive deficits via
altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation
could be beneficial in early AD.
