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. 2022 Jun 22;12:257. doi: 10.1038/s41398-022-02024-7

Table 1.

Evidence of neuronal hyperexcitability in patients, animal and cell models of Alzheimer’s disease.

Study type/ Neuronal subtype Model/Group of study Functional phenotype Methodology Reference
Human studies
Clinical study 16 non-demented APOE4 carriers (two APOE4/4 and 14 APOE3/4 subjects) Increased activity of parahippocampal, left hippocampal, parietal, temporal, and prefrontal regions of APOE4 carriers fMRI [18]
14 non-demented APOE3/3 individuals
Clinical study Ten controls Increased hippocampal activity in MCI individuals compared to controls fMRI [9]
Nine mild MCI patients Decreased hippocampal and entorhinal activity in AD patients compared to controls
Ten AD patients
Clinical study 90 controls Increased activity of the hippocampus, frontal, and temporal lobes of asymptomatic offspring of AD patients fMRI [17]
95 asymptomatic offspring of AD patients
Clinical study 15 controls Increased hippocampal activity in less impaired MCI subjects compared to controls fMRI [8]
15 less impaired MCI patients Decreased hippocampal activity in more impaired MCI and mild AD subjects compared to control
12 more impaired MCI patients
Ten mild AD patients
Clinical study 19 controls Increased activity in the posterior hippocampal, parahippocampal and fusiform regions of MCI patients vs controls fMRI [10]
14 subjects with MCI Brain activity of AD patients was not significantly different from control
11 patients with mild AD
Animal models
Frontal, central, parietal, and occipital cortices of freely moving control and hAPP-J20 mice 3–7 months non-transgenic mice (n = not specified)  hAPP-J20 mice had frequent generalized cortical epileptiform discharges, which were absent in the control EEG [26]
3–7 months mice expressing hAPP
Swedish and Indiana mutations (n = 6 mice)
Neurons of L2/3 frontal cortex of live control and APP23xPS45 mice 6–10 months control mice (n = 10 mice; 564 neurons) Greater number of hyperactive (>4 transients/min) neurons in APPswe/PS1G384 mice Calcium imaging [11]
6–10 months APPswe/PS1G384A mice (n = 20 mice; 564 neurons)
L2/3 pyramidal neurons of cortical slices 3–4.5 months non-transgenic mice (n = 10 mice; 6 neurons) Current injection induced action potential firing in APdE9 mice at subthreshold stimulus compared to controls Whole-cell patch-clamp [15]
Frontal cortex of freely moving control and APdE9 mice 3–4.5 months mice harboring APPswe and PSEN1dE9 mutations 25–65% of APdE9 mice had seizures, while none of the control animals exhibited this phenotype EEG
(n = 20 mice; nine neurons)
Pyramidal neurons of lateral amygdala slices of APOE3 and APOE4 mice 1 and 7 months human APOE3/E3 knock-in mice (n = 11 mice; 23 neurons) Reduced frequency of spontaneous excitatory postsynaptic currents in APOE4/E4 mice Whole-cell patch-clamp [32]
1 and 7 months human APOE4/E4 knock-in mice (n = 12 mice; 28 neurons)
CA1 pyramidal neurons of live control and APP23xPS45 mice 1–2 months control mice (n = 6 mice; 693 neurons) Greater number of hyperactive (>20 transients/min) neurons in APPswe/PS1G384A mice Calcium imaging [28]
1–2 months APPswe/PS1G384A mice (n = 7 mice; 818 neurons)
6–7 months control mice (n = 5 mice; 312 neurons)
6–7 months APPswe/PS1G384A mice (n = 5 mice; 349 neurons)
Neurons of CA1 hippocampal slices of APP/PS1 mice 10–14 months control mice (n = 16 mice; 35–75 neurons) Higher frequency of spontaneous action potential in APPswe/PS1M146V animals Whole-cell patch-clamp [12]
10–14 months APPswe/PS1M146V mice (n = 16 mice; 44–69 neurons)
Cortex and hippocampus of live control and Tg2576 mice 5wo WT mice (n = 17) Synchronized transient spike-like events were detected in Tg2576 mice but absent in WT mice EEG [29]
5wo APPswe mice (n = 9)
Neurons of L2/3 frontal cortex of live control and APP23xPS45 mice 10–14 months control mice (n = 9 mice; 226 neurons) Greater number of hyperactive (>4 transients/min) neurons in APPswe/PS1G384A Calcium imaging [27]
10–14 months APPswe/PS1G384A (n = 10 mice; 260 neurons)
2D and 3D cell culture models
iPSC-derived neurons iPSCs from one sporadic AD patient Sporadic AD neurons had spontaneous Ca2+ responses and control neurons remained inactive in the absence of stimulus Calcium imaging [13]
(n > 30 from three independent experiments) iPSCs from one healthy individual
iPSC-derived neurons APOE4/4 iPSCs from one sporadic AD patient Higher frequency of miniature excitatory postsynaptic current in APOE4/4 neurons Whole-cell patch-clamp [37]
(n = 7–9 from three independent cultures) APOE3/3 isogenic control iPSCs
3D coculture of iPSC-derived neurons and astrocytes (n = >3 independent experiments) Lentiviral-transduced human neural progenitor cells expressing both Increased spontaneous Ca2+ transients in FAD neurons Calcium imaging [38]
Swedish and London APP
mutations
Control human neural progenitor cells
2D and 3D cultures of cortical neurons iPSCs from one healthy individual Higher frequency of spontaneous action potential in 2D AD neurons Whole-cell patch-clamp [14]
(n = 13) iPSCs from healthy individuals edited by CRISPR/Cas9 to express Increase in spontaneous action potential firing rate in 3D AD neurons MEA
APPswe or PS1M146V mutation
iPSCs from another healthy individual
iPSCs from healthy individuals edited by TALEN to express PS1dE9 mutation

AD Alzheimer’s disease, EEG electroencephalogram, FAD familial Alzheimer’s disease, fMRI functional magnetic resonance imaging, iPSC induced pluripotent stem cells, MCI mild cognitive impairment, MEA microelectrode array, WT wild-type.