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Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration.
Brain Res. 2014 Jan 16; 1543:253-62.BR

Abstract

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.

Authors+Show Affiliations

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.H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark.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.H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24231553

Citation

Laursen, Bettina, et al. "Impaired Hippocampal Acetylcholine Release Parallels Spatial Memory Deficits in Tg2576 Mice Subjected to Basal Forebrain Cholinergic Degeneration." Brain Research, vol. 1543, 2014, pp. 253-62.
Laursen B, Mørk A, Plath N, et al. Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration. Brain Res. 2014;1543:253-62.
Laursen, B., Mørk, A., Plath, N., Kristiansen, U., & Bastlund, J. F. (2014). Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration. Brain Research, 1543, 253-62. https://doi.org/10.1016/j.brainres.2013.10.055
Laursen B, et al. Impaired Hippocampal Acetylcholine Release Parallels Spatial Memory Deficits in Tg2576 Mice Subjected to Basal Forebrain Cholinergic Degeneration. Brain Res. 2014 Jan 16;1543:253-62. PubMed PMID: 24231553.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration. AU - Laursen,Bettina, AU - Mørk,Arne, AU - Plath,Niels, AU - Kristiansen,Uffe, AU - Bastlund,Jesper Frank, Y1 - 2013/11/11/ PY - 2013/03/20/received PY - 2013/10/28/revised PY - 2013/10/29/accepted PY - 2013/11/16/entrez PY - 2013/11/16/pubmed PY - 2014/8/19/medline KW - ACh KW - AD KW - APP KW - Acetylcholine KW - Alzheimer's disease KW - Alzheimer’s disease KW - Aβ KW - BFCD KW - ChAT KW - Cognitive deficit KW - HPLC KW - M2R KW - Mu p75-saporin KW - PS1 KW - PS2 KW - SAP KW - T-CAT KW - T-maze continuous alternation task. KW - Tg2576 KW - acetylcholine KW - amyloid beta KW - amyloid precursor protein KW - basal forebrain cholinergic degeneration KW - choline acetyltransferase KW - high performance liquid chromatography KW - icv KW - intracerebroventricular KW - mu p75-saporin KW - muscarinic acetylcholine receptor 2 KW - presenilin 1 KW - presenilin 2 KW - wild type littermate KW - wt SP - 253 EP - 62 JF - Brain research JO - Brain Res VL - 1543 N2 - 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. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/24231553/Impaired_hippocampal_acetylcholine_release_parallels_spatial_memory_deficits_in_Tg2576_mice_subjected_to_basal_forebrain_cholinergic_degeneration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(13)01465-0 DB - PRIME DP - Unbound Medicine ER -