Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5×FAD Mice.
Aging
/ metabolism
Alzheimer Disease
/ genetics
Amyloid beta-Protein Precursor
/ genetics
Animals
Calcium
/ metabolism
Female
Hippocampus
/ cytology
Humans
Male
Mice
Mice, Transgenic
Morris Water Maze Test
Neuronal Plasticity
Neurons
/ metabolism
Optical Imaging
Patch-Clamp Techniques
Plaque, Amyloid
/ metabolism
Presenilin-1
/ genetics
Sex Factors
Spatial Learning
Spatial Memory
5×FAD
Alzheimer’s disease
afterhyperpolarization
aging
calcium
electrophysiology
hippocampus
hyperactivity
intracellular
sex
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2020
2020
Historique:
pubmed:
10
11
2020
medline:
30
9
2021
entrez:
9
11
2020
Statut:
ppublish
Résumé
In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD.
Sections du résumé
BACKGROUND
In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker.
OBJECTIVE
Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old.
METHODS
Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging.
RESULTS
Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation.
CONCLUSION
Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD.
Identifiants
pubmed: 33164928
pii: JAD200109
doi: 10.3233/JAD-200109
pmc: PMC7836067
doi:
Substances chimiques
Amyloid beta-Protein Precursor
0
PSEN1 protein, human
0
Presenilin-1
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1419-1438Subventions
Organisme : NIA NIH HHS
ID : R01 AG052934
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG058171
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG057461
Pays : United States
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