Behaviour Hallmarks in Alzheimer’s Disease 5xFAD Mouse Model

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6766 - 6766

Опубликована: Июнь 20, 2024

The 5xFAD transgenic mouse model widely used in Alzheimer’s disease (AD) research recapitulates many AD-related phenotypes with a relatively early onset and aggressive age-dependent progression. Besides developing amyloid peptide deposits alongside neuroinflammation by the age of 2 months, as well exhibiting neuronal decline 4 months that intensifies 9 these mice manifest broad spectrum behavioural impairments. In this review, we present extensive repertoire dysfunctions mice, organised into four categories: motor skills, sensory function, learning memory abilities, neuropsychiatric-like symptoms. problems, associated agility reflex movements, balance coordination, skeletal muscle typically arise time reach age. function (such taste, smell, hearing, vision) starts to deteriorate when buildups spread related anatomical structures. cognitive functions, encompassing such visual recognition, associative, spatial working, reference learning, show signs from 6 Concerning symptoms, comprising apathy, anxiety depression, willingness for exploratory behaviour, it is believed motivational changes emerge approximately Unfortunately, numerous studies different laboratories are often contradictory on conclusions drawn identification age, making preclinical rodent models not easily translatable humans. This variability likely due range factors animals themselves, housing husbandry conditions, experimental settings. forthcoming studies, greater clarity details conducting testing could minimise inconsistencies ensure reliability reproducibility results.

Язык: Английский

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Age-related changes in species-typical behaviours in the 5xFAD mouse model of Alzheimer’s disease from 4 to 16 months of age

Behavioural Brain Research, Год журнала: 2024, Номер 465, С. 114970 - 114970

Опубликована: Март 24, 2024

Alzheimer's disease (AD) patients show age-related decreases in the ability to perform activities of daily living and decline these is related severity neurobiological deterioration underlying disease. The 5xFAD mouse model AD shows impairments sensory- motor cognitive function, but little known about changes species-typical behaviours that may patients. Therefore, we examined used as indices exploration (rearing) compulsivity (grooming) across six tests anxiety-like behaviour or function female mice from 3-16 months age. Robust rearing were found all after 9 age, although few differences observed grooming. A fine-scale analysis grooming, however, revealed a previously unresolved spatially restricted pattern grooming at 13-16 We then home-cage, impaired nest building ages tested. Lastly, relationship between reduced species typical presentation freezing behaviour, commonly measure memory for conditioned fear. These results showed along with sensory-motor have robust behaviours. help patients, provide useful behavioural phenotypes evaluating pre-clinical efficacy novel therapeutics AD.

Язык: Английский

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Early emergence of motivational and hedonic feeding deficits in the TgF344-AD rat model of Alzheimer’s disease

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Апрель 28, 2025

Alzheimer's disease (AD) is characterized by progressive cognitive decline and has a long prodromal phase during which subclinical deficits neuropsychiatric symptoms may begin to emerge. Apathy, defined as lack of motivation or volition, increasingly recognized core feature potentially early marker AD. Despite its significance, apathy-like behavior been underexplored in transgenic models We performed longitudinal analysis using the well-established TgF344-AD rat model. compared male female wildtype rats on hedonic (palatable food intake) motivational (progressive ratio) assays (3-4 months), intermediate (6-7 later (9-10 months) stages adulthood. found that exhibited persistent feeding, emerging at 3-4 months 6-7 months, respectively. During battery tests conducted after 12-14 age, were impaired spatial working memory but also showed wide-ranging exploratory behavior, be indicative an loss investigatory drive. Our findings highlight valuable model for studying AD underscore need consider sex differences research better understand this disease.

Язык: Английский

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Apathy-like behaviour in tau mouse models of Alzheimer’s disease and frontotemporal dementia

Behavioural Brain Research, Год журнала: 2023, Номер 456, С. 114707 - 114707

Опубликована: Окт. 9, 2023

Apathy is the most common behavioural and psychological symptom in Alzheimer's disease (AD) other neurodegenerative diseases including frontotemporal dementia (FTD) Parkinson's (PD). In patients, apathy can include symptoms of loss motivation, initiative, interest, listlessness, indifference, flattening emotions, absence drive passion. Researchers have later refined this to a reduction goal direct behaviours. animals, specific apathy-like behaviour been modelled directed or nest-building which are seen as indicative proxies for motivation daily activities. present study protocol was established using four different inbred mouse strains (CD1, BALB/c, C57Bl/6J, C3H) before assessing AD FTD tau transgenic mice Line 1 (L1) 66 (L66) paradigm. Female aged 5 - 6 months were assessed home cage over period 7 days with scored by three independent experimenters at intervals 1-, 2- 7-days post nestlet introduction. Inbred displayed levels nesting behaviour. BALB/c more proficient than CD1 C3H mice, while all similar day 7. models, L66 presented impaired compared wild-type on 2 (not 7), whereas L1 performed like days. Anhedonia measured sucrose preference test only observed L66. low scores phenotypes. Differences evident between models likely due human species expressed these mice.

Язык: Английский

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Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(9), С. 6082 - 6093

Опубликована: Июль 5, 2024

Abstract INTRODUCTION Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation critical connecting amyloid beta (Aβ) and tau‐based degenerative events early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT‐PET radiotracer, [ 11 C]MPC‐6827, multiple established AD mouse models. METHODS Longitudinal PET, biodistribution, autoradiography, immunohistochemistry, behavioral studies were conducted at time points APPswe/PSEN1dE9 (APP/PS1), P301S‐PS19 (P301S), 5xFAD, age‐matched control mice. RESULTS C]MPC‐6827 brain showed significant increases APP/PS1, P301S, 5xFAD mice compared to controls. correlated positively with immunohistochemistry results negatively behavior data. DISCUSSION Our study demonstrated longitudinal PET models the first time. Strong correlations between biomarker data underscored interplay destabilization, amyloid, tau pathology AD. These suggest as a promising tool monitoring progression. Highlights using (AD) revealed an onset microtubule dysregulation, radiotracer uptake evident from 2 4 months age. Intra‐group analysis progressive increase increasing burden, supported by molecular pathological markers. its efficacy detecting alterations preceding observable models, suggesting potential imaging. The inclusion model further elucidated impact toxicity on inducing hyperphosphorylation‐mediated highlighting versatility delineating various aspects pathology. provides immediate clarity high microtubule‐based brains setting, which directly informs clinical utility Aβ/tau‐based studies.

Язык: Английский

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Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling

GeroScience, Год журнала: 2024, Номер unknown

Опубликована: Сен. 13, 2024

Язык: Английский

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Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer disease mouse model via enhancing neurotrophic and synaptic signaling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 16, 2024

Abstract INTRODUCTION Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through secretion of skeletal originating factors (‘myokines’) with neuroprotective properties. However, precise mechanisms underlying these benefits in context Alzheimer’s disease (AD) remain poorly understood. METHODS To investigate signaling response to amyloid β (Aβ)- induced toxicity, we generated 5xFAD transgenic female mice enhanced (5xFAD;cTFEB;HSACre) at prodromal (4-months old) late (8-months symptomatic stages. RESULTS TFEB overexpression reduced Aβ plaque accumulation cortex hippocampus both ages rescued behavioral neurocognitive deficits 8- months-old mice. These changes were associated transcriptional protein remodeling neurotrophic synaptic integrity, partially due CNS-targeting myokine prosaposin (PSAP). DISCUSSION Our findings implicate as a novel pathway against pathogenesis AD.

Язык: Английский

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Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Disease Models & Mechanisms, Год журнала: 2023, Номер 16(10)

Опубликована: Сен. 29, 2023

ABSTRACT Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes a physiological knock-in mouse model carrying pathogenic FUSDelta14 homozygosity. RNA sequencing multiple organs aimed to identify pathways altered by mutant transcriptome, including metabolic tissues, given link between ALS-frontotemporal dementia and metabolism. Few genes were commonly across all most affected generally tissue specific. Phenotypic assessment mice revealed alterations related pathway changes identified. Magnetic resonance imaging brain scans histological characterisation that homozygous brains smaller than heterozygous wild-type displayed significant morphological alterations, thinner cortex, reduced neuronal number increased gliosis, which correlated with early cognitive impairment fatal seizures. These findings show disease aetiology variants can include both neurodevelopmental alterations.

Язык: Английский

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Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 23, 2024

Abstract Immunotherapy of Alzheimer’s disease (AD) is a promising approach to reduce the accumulation amyloid-beta (Aβ), critical event in onset disease. Targeting group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important controlling Aβ production, although their respective contribution remains unclear due lack selective tools. Here, we show that enhancing receptor activity increases 1-42 peptide production whereas activation mGlu3 has no effect. We such difference likely results from direct interaction APP with but not prevents amyloidogenic cleavage peptides production. then chronic treatments AD model 5xFAD mice brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation exacerbated memory deficits, had effect control mice. Our confirm mGluR2 exacerbates development, suggesting therapeutic benefices obtained blockers this receptor. study also provides proof-of-concept administration nanobodies targeting neuroreceptors can envisioned treat brain diseases.

Язык: Английский

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Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 101(4), С. 1217 - 1226

Опубликована: Окт. 8, 2024

Background: Apathy is a state of decreased interest, lack initiative, reduced goal-directed activity and blunted emotional responses. one the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) also relatively omnipresent individuals Down syndrome (DS). Little known about apathy-like behaviors rodent models AD DS. Objective: This study aimed to characterize aging two established DS mouse models: Ts65Dn Dp16. Methods: A battery behavioral tests including nestlet shredding, marble burying, nest building, burrowing were performed examine behaviors. Individual z-scores for each test, composite z-score behavior analyzed all mice from these tests. Results: Analysis individual test results revealed significant compared WT controls. In contrast, Dp16 did not exhibit Conclusions: Our first highlights difference between model regarding manifestations aging.

Язык: Английский

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