TY - JOUR

T1 - Decanoic Acid Rescues Differences in AMPA-Mediated Calcium Rises in Hippocampal CA1 Astrocytes and Neurons in the 5xFAD Mouse Model of Alzheimer's Disease

AU - Abghari, Mina

AU - Vu, Jenny Thythy Cecilia Mai

AU - Eckberg, Ninna

AU - Aldana, Blanca I

AU - Kohlmeier, Kristi A

PY - 2023

Y1 - 2023

N2 - Alzheimer's disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ 42), which is believed to play a role in cellular damage and signaling changes in AD. Decanoic acid has been shown to be therapeutic in AD. Glutamatergic signaling within neurons and astrocytes of the CA1 region of the hippocampus is critical in cognitive processes, and previous work has indicated deficiencies in this signaling in a mouse model of AD. In this study, we investigated glutamate-mediated signaling by evaluating AMPA-mediated calcium rises in female and male CA1 neurons and astrocytes in a mouse model of AD and examined the potential of decanoic acid to normalize this signaling. In brain slices from 5xFAD mice in which there are five mutations leading to increasing levels of Aβ 42, AMPA-mediated calcium transients in CA1 neurons and astrocytes were significantly lower than that seen in wildtype controls in both females and males. Interestingly, incubation of 5xFAD slices in decanoic acid restored AMPA-mediated calcium levels in neurons and astrocytes in both females and males to levels indistinguishable from those seen in wildtype, whereas similar exposure to decanoic acid did not result in changes in AMPA-mediated transients in neurons or astrocytes in either sex in the wildtype. Our data indicate that one mechanism by which decanoic acid could improve cognitive functioning is through normalizing AMPA-mediated signaling in CA1 hippocampal cells.

AB - Alzheimer's disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ 42), which is believed to play a role in cellular damage and signaling changes in AD. Decanoic acid has been shown to be therapeutic in AD. Glutamatergic signaling within neurons and astrocytes of the CA1 region of the hippocampus is critical in cognitive processes, and previous work has indicated deficiencies in this signaling in a mouse model of AD. In this study, we investigated glutamate-mediated signaling by evaluating AMPA-mediated calcium rises in female and male CA1 neurons and astrocytes in a mouse model of AD and examined the potential of decanoic acid to normalize this signaling. In brain slices from 5xFAD mice in which there are five mutations leading to increasing levels of Aβ 42, AMPA-mediated calcium transients in CA1 neurons and astrocytes were significantly lower than that seen in wildtype controls in both females and males. Interestingly, incubation of 5xFAD slices in decanoic acid restored AMPA-mediated calcium levels in neurons and astrocytes in both females and males to levels indistinguishable from those seen in wildtype, whereas similar exposure to decanoic acid did not result in changes in AMPA-mediated transients in neurons or astrocytes in either sex in the wildtype. Our data indicate that one mechanism by which decanoic acid could improve cognitive functioning is through normalizing AMPA-mediated signaling in CA1 hippocampal cells.

KW - Male

KW - Mice

KW - Female

KW - Animals

KW - Alzheimer Disease/genetics

KW - Amyloid beta-Peptides/metabolism

KW - Astrocytes/metabolism

KW - Calcium

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology

KW - Neurodegenerative Diseases

KW - Hippocampus/metabolism

KW - Neurons/metabolism

KW - Disease Models, Animal

U2 - 10.3390/biom13101461

DO - 10.3390/biom13101461

M3 - Journal article

C2 - 37892143

VL - 13

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 10

M1 - 1461

ER -