REGION-SPECIFIC NEURON AND SYNAPSE LOSS IN THE HIPPOCAMPUS OF APPSL/PS1 KNOCK-IN MICE.
Transgenic mouse models with knock-in (KI) expression of human mutant amyloid precursor protein (APP) and/or human presenilin 1 (PS1) may be helpful to elucidate the cellular consequences of APP and PS1 misprocessing in the aging brain. Age-related alterations in total numbers of neurons and in numbers of synaptophysin-immunoreactive presynaptic boutons (SIPB), as well as the amyloid plaque load were analyzed in the hippocampal dentate gyrus (DG), CA3, and CA1-2 of 2- and 10-month-old APPSL/PS1 homozygous KI, APPSL(expressing human mutant APP751 carrying the Swedish [K670N/M671L] and London [V717I] mutations under Thy-1 promoter), and PS1 homozygous KI mice (expressing human PS1 mutations [M233T and L235P]). APPSL/PS1 homozygous KI mice, but neither APPSLmice nor PS1 homozygous KI mice, showed substantial age-related loss of neurons (-47.2%) and SIPB (-22.6%), specifically in CA1-2. PS1 homozygous KI mice showed an age-related increase in hippocampal granule cell numbers (+37.9%). Loss of neurons and SIPB greatly exceeded the amount of local extracellular Aβ aggregation and astrocytes, whereas region-specific accumulation of intraneuronal Aβ preceded neuron and synapse loss. An age-related increase in the ratio of SIPB to neuron numbers in CA1-2 of APPSL/PS1 homozygous KI mice was suggestive of compensatory synaptic plasticity. These findings indicate a region-selectivity in intra- and extraneuronal Aβ accumulation in connection with neuron and synapse loss in the hippocampus of APPSL/PS1 homozygous KI mice.
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands ; European Graduate School of Neuroscience (EURON), 6200 MD Maastricht, The Netherlands.
Ivona
I
Brasnjevic
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands.
Roy
R
Lardenoije
Department of Anatomy II, Institute of Anatomy, Ludwig-Maximilians-University, 80336 Munich, Germany.
Christoph
C
Schmitz
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands ; European Graduate School of Neuroscience (EURON), 6200 MD Maastricht, The Netherlands.
Nicolien
N
Van Der Kolk
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Dara L
DL
Dickstein
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, 791-0295 Ehime, Japan.
Hisaaki
H
Takahashi
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Patrick R
PR
Hof
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands ; European Graduate School of Neuroscience (EURON), 6200 MD Maastricht, The Netherlands.
Harry W M
HW
Steinbusch
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands ; European Graduate School of Neuroscience (EURON), 6200 MD Maastricht, The Netherlands.
Bart P F
BP
Rutten
Alzheimer’s disease; Amyloid precursor protein; Hippocampus; Image analysis; Neuron loss; Presenilin-1; Stereology; Synapse loss