Preclinical models of disease and multimorbidity with focus upon cardiovascular disease and dementia

Shabir, Osman; Moll, Tobias; Matuszyk, Martyna M.; Eyre, Beth; Dake, Manmohi D; Berwick, Jason; Francis, Sheila

doi:10.1016/j.mad.2020.111361

Cited by 9 publications

(5 citation statements)

References 248 publications

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“…AD is characterised by two hallmark pathologies in the brain: (i) the formation of extracellular amyloid beta (Aβ) plaques and (ii) deposits of neurofibrillary tangles of hyperphosphorylated tau protein [ 37 ]. These neuropathological changes are accompanied by glial cell activation, release of pro-inflammatory mediators and neuronal death, leading to brain atrophy [ 38 ]. Much like ALS and PD, MLRs are strongly linked with AD pathophysiology.…”

Section: Mlr Function Is Linked To Neurodegenerative Diseasesmentioning

confidence: 99%

Membrane lipid raft homeostasis is directly linked to neurodegeneration

Marshall

Soni

Zhang

et al. 2021

Essays in Biochemistry

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Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.

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Section: Mlr Function Is Linked To Neurodegenerative Diseasesmentioning

confidence: 99%

Membrane lipid raft homeostasis is directly linked to neurodegeneration

Marshall

Soni

Zhang

et al. 2021

Essays in Biochemistry

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“…Employed in vitro and in vivo PD models mimic the chronic progressive, slow sometimes relapse like progression of neuronal dying to a limited extent. Toxin models with, e.g., 6-OH-dopamine, rotenone, or MPTP application, induce nigrostriatal dopamine deficiency [98]. They only reflect the motor impairment in PD and often result from an acute event after a singular toxin administration.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Müller

Mueller

Riederer

2021

Cells

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Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.

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“…[12][13][14] Dementia models can be investigated using dementia risk factor-related tests, or alternatively, can be combined with complementary models of dementia risk factors (transgenic animals, surgical interventions, drug treatments, or other interventions) to further explore the intersection of dementia risk and pathology. 15 In this narrative review, we consider the role of laboratory science in understanding modifiable dementia risk, specifically focusing on how studies in experimental models can be interpreted and where model systems can fill the gaps in knowledge that are challenging to answer with human studies. We focus primarily on rodent studies but include examples from emerging model systems such as iPSC-derived cells.…”

Section: Introductionmentioning

confidence: 99%

“… 12 , 13 , 14 Dementia models can be investigated using dementia risk factor‐related tests, or alternatively, can be combined with complementary models of dementia risk factors (transgenic animals, surgical interventions, drug treatments, or other interventions) to further explore the intersection of dementia risk and pathology. 15 …”

Section: Introductionmentioning

confidence: 99%

“…Second and more commonly, animal models of dementia are used; these are animals which have been genetically modified (e.g., to overexpress human genes) or neurobiologically altered (e.g., through injection of engineered human peptides) to develop human‐like dementia‐related pathology 12–14 . Dementia models can be investigated using dementia risk factor‐related tests, or alternatively, can be combined with complementary models of dementia risk factors (transgenic animals, surgical interventions, drug treatments, or other interventions) to further explore the intersection of dementia risk and pathology 15 …”

Section: Introductionmentioning

confidence: 99%

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Experimental laboratory models as tools for understanding modifiable dementia risk

Sinclair,

Canty,

Ziebell

et al. 2024

Alzheimer's & Dementia

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Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early‐life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies.Highlights Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

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Preclinical models of disease and multimorbidity with focus upon cardiovascular disease and dementia

Cited by 9 publications

References 248 publications

Membrane lipid raft homeostasis is directly linked to neurodegeneration

Membrane lipid raft homeostasis is directly linked to neurodegeneration

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Experimental laboratory models as tools for understanding modifiable dementia risk

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