TY  - JOUR
AU  - Viana-da-Silva, Silvia
AU  - Haberl, Matthias
AU  - Gaur, Kshitij
AU  - Patel, Rina
AU  - Narayan, Gautam
AU  - Ledakis, Max
AU  - Fu, Maylin L
AU  - de Castro Vieira, Miguel
AU  - Koo, Edward H
AU  - Leutgeb, Jill K
AU  - Leutgeb, Stefan
TI  - Localized APP expression results in progressive network dysfunction by disorganizing spike timing.
JO  - Neuron
VL  - 112
IS  - 1
SN  - 0896-6273
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2024-00045
SP  - 124 - 140.e6
PY  - 2024
AB  - Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.
KW  - Mice
KW  - Humans
KW  - Animals
KW  - Aged
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Hippocampus: metabolism
KW  - Neurons: physiology
KW  - Alzheimer Disease: metabolism
KW  - Synapses: physiology
KW  - Mice, Transgenic
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - Alzheimer’s disease (Other)
KW  - amyloid precursor protein (Other)
KW  - hippocampus (Other)
KW  - phase precession (Other)
KW  - spike timing (Other)
KW  - theta oscillations (Other)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10877582
C6  - pmid:37909036
DO  - DOI:10.1016/j.neuron.2023.10.001
UR  - https://pub.dzne.de/record/266787
ER  -