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Bales, K.R. et al.

Bales, Tzavara, Wu, Wade, Bymaster, Paul, Nomikos,

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody.

Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid beta ( A beta) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human A beta peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked A beta-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-A beta antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the A beta peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-A beta antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.[1]

References

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. Bales, K.R., Tzavara, E.T., Wu, S., Wade, M.R., Bymaster, F.P., Paul, S.M., Nomikos, G.G. J. Clin. Invest. (2006) [Pubmed]

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