Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration.
The Alzheimer's disease (AD) mouse model Tg2576 overexpresses an AD associated mutant variant of human APP and accumulates amyloid beta (Aβ) in an age-dependent manner. Using the selective cholinergic immunotoxin mu p75-saporin (SAP), we induced a partial basal forebrain cholinergic degeneration (BFCD) in 3 months old male Tg2576 mice to co-express cholinergic degeneration with Aβ overexpression as these characteristics constitutes key hallmarks of AD. At 9 months, SAP lesioned Tg2576 mice were cognitively impaired in two spatial paradigms addressing working memory and mid to long-term memory. Conversely, there was no deterioration of cognitive functioning in sham lesioned Tg2576 mice or wild type littermates (wt) receiving the immunotoxin. At 10 months of age, release of acetylcholine (ACh) was addressed by microdialysis in conscious mice. Scopolamine-induced increases in hippocampal ACh efflux was significantly reduced in SAP lesioned Tg2576 mice compared to sham lesioned Tg2576 mice. Intriguingly, there was no significant difference in ACh efflux between wt treatment groups. Following SAP treatment, choline acetyltransferase activity was reduced in the hippocampus and frontal cortex and the reduction was comparable between groups. Our results suggest that partial BFCD acts collectively with increased levels of Aβ to induce cognitive decline and to compromise cholinergic release. Tg2576 mice with BFCD may constitute a new and suitable AD mouse model to study the interrelations between cholinergic deficits and amsyloid deposition.
H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: xbc@lundbeck.com.
Bettina
B
Laursen
H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark.
Arne
A
Mørk
H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark.
Niels
N
Plath
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Uffe
U
Kristiansen
H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark.
Jesper Frank
JF
Bastlund
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D018782:Maze Learning; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology*; D053764:Presenilin-1 / Q000235:genetics; D016548:Prosencephalon / Q000473:pathology*; D021641:Recognition, Psychology / Q000502:physiology; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D000076985:Saporins
D016564:Amyloid beta-Protein Precursor; D000922:Immunotoxins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D054789:Ribosome Inactivating Proteins, Type 1; D002795:Choline O-Acetyltransferase; D000076985:Saporins; D000109:Acetylcholine
ACh; AD; APP; Acetylcholine; Alzheimer's disease; Alzheimer’s disease; Aβ; BFCD; ChAT; Cognitive deficit; HPLC; M2R; Mu p75-saporin; PS1; PS2; SAP; T-CAT; T-maze continuous alternation task.; Tg2576; acetylcholine; amyloid beta; amyloid precursor protein; basal forebrain cholinergic degeneration; choline acetyltransferase; high performance liquid chromatography; icv; intracerebroventricular; mu p75-saporin; muscarinic acetylcholine receptor 2; presenilin 1; presenilin 2; wild type littermate; wt