Transcending the amyloid-beta dominance paradigm in Alzheimer’s disease: An exploration of behavioural, metabolic, and gut microbiota phenotypes in 5xFAD mice
Neurobiology of Disease. 2023-10-01; 187: 106295
DOI: 10.1016/j.nbd.2023.106295
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https://www.bordeaux-neurocampus.fr/12242
Medina-Vera D(1), Zambrana-Infantes EN(2), López-Gambero AJ(3), Verheul-Campos
J(4), Santín LJ(2), Baixeras E(5), Suarez J(6), Pavon FJ(7), Rosell-Valle C(8),
de Fonseca FR(9).
Author information:
(1)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain; Facultad de Ciencias, Campus de
Teatinos s/n, Universidad de Málaga, 29010 Málaga, Spain; Facultad de Medicina,
Campus de Teatinos s/n, Universidad de Málaga, 29010 Málaga, Spain; Unidad de
Gestión Clínica del Corazón-CIBERCV (Enfermedades Cardiovasculares), Hospital
Universitario Virgen de la Victoria, 29010 Málaga, Spain.
(2)Departamento de Psicobiología y Metodología de las Ciencias del
Comportamiento, Facultad de Psicología, Universidad de Málaga, 29010 Málaga,
Spain.
(3)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain; University of Bordeaux, INSERM,
Neurocentre Magendie, U1215, 33000 Bordeaux, France.
(4)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain.
(5)Departamento de Bioquímica y Biología Molecular, Facultad de Medicina,
Universidad de Málaga, 29010 Málaga, Spain.
(6)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain; Departamento de Anatomía Humana,
Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de
Málaga, 29010 Málaga, Spain.
(7)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain; Unidad de Gestión Clínica del
Corazón-CIBERCV (Enfermedades Cardiovasculares), Hospital Universitario Virgen
de la Victoria, 29010 Málaga, Spain.
(8)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain. Electronic address:
.
(9)Instituto de Investigación Biomédica de Málaga y Plataforma en
Nanomedicina-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional
Universitario de Málaga, 29010 Málaga, Spain. Electronic address:
.
The amyloid cascade hypothesis is widely accepted as an explanation for the
neuropathological changes in Alzheimer’s disease (AD). However, the role of
amyloid-beta (Aβ) as the sole cause of these changes is being questioned. Using
the 5xFAD mouse model of AD, we investigated various factors contributing to
neuropathology, including genetic load (heterozygous (HTZ) versus homozygous
(HZ) condition), behavioural phenotype, neuropathology markers, metabolic
physiology, and gut microbiota composition at early (5 months of age) and late
(12 months of age) stages of disease onset, and considering both sexes. At
5 months of age, both HTZ and HZ mice exhibited hippocampal alterations
associated with Aβ accumulation, leading to increased neuroinflammation and
disrupted PI3K-Akt pathway. However, only HZ mice showed cognitive impairment in
the Y-maze and Morris water maze tests, worsening with age. Dysregulation of
both insulin and insulin secretion-regulating GIP peptide were observed at
5 months of age, disappearing later. Circulating levels of metabolic-regulating
hormones, such as Ghrelin and resisting helped to differentiates HTZ mice from
HZ mice. Differences between HTZ and HZ mice were also observed in gut
microbiota composition, disrupted intestinal barrier proteins, and increased
proinflammatory products in the intestine. These findings suggest that cognitive
impairment in 5xFAD mice may not solely result from Aβ aggregation. Other
factors, including altered PI3K-Akt signalling, disrupted insulin-linked
metabolic pathways, and changes in gut microbiota, contribute to disease
progression. Targeting Aβ deposition alone may not suffice. Understanding AD
pathogenesis and its multiple contributing factors is vital for effective
therapies.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2023.106295
PMID: 37717663
Conflict of interest statement: Declaration of Competing Interest The authors
have no relevant financial or non-financial interests to disclose.