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.
Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. KRBales@Lilly.com
Kelly R
KR
Bales
Eleni T
ET
Tzavara
Su
S
Wu
Mark R
MR
Wade
Frank P
FP
Bymaster
Steven M
SM
Paul
George G
GG
Nomikos
D000109:Acetylcholine / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007858:Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000906:Antibodies; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D000109:Acetylcholine