Comparative neuropathology in aging primates: A perspective

Freire-Cobo, Carmen; Edler, Melissa K.; Varghese, Merina; Munger, Emily L.; Laffey, Jessie; Raia, Sophia; In, Selena S; Wicinski, Bridget; Medalla, Maria; Perez, Sylvia E.; Mufson, Elliott J.; Erwin, J.; Guevara, Elaine E.; Sherwood, Chet C.; Luebke, Jennifer I.; Lacreuse, Agnès; Raghanti, Mary Ann; Hof, Patrick R.

doi:10.1002/ajp.23299

Cited by 17 publications

(15 citation statements)

References 260 publications

(511 reference statements)

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“…A decrease in reelin‐expressing neurons has been identified in layer II of the entorhinal cortex in aged macaques with memory deficits, suggesting that select neuronal classes may be vulnerable to cognitive aging (Long et al., 2020). While total neuron numbers may remain relatively preserved, there is an age‐related loss of dendritic spines, irregularities in dendritic arborization, irregularities in spine distribution, and number and morphology of synapses in macaques, patas monkeys, marmosets, and mouse lemurs (Freire‐Cobo et al., 2021).…”

Section: Brain Aging In Humans and Nonhuman Primatesmentioning

confidence: 99%

“…Braak et al, 2006;H. Braak & Braak, 1991;Bierer et al, 1995;Bennett et al, 2006;Knopman et al, 2003;Price et al, 2009;Tanprasertsuk et al, 2019;Tsartsalis et al, 2018;Freire-Cobo et al, 2021;Edler et al, 2017;Perez et al, 2013;Perez et al, 2016 Neurons , 1997;Serrano-Pozo, Mielke, et al, 2011;Terry et al, 1991;Cochran et al, 2014;Hyman et al, 1984;Morrison et al, 1998;Morrison & Hof, 2002;Stranahan & Mattson, 2010;Whitehouse et al, 1982;Chin et al, 2007;Bussière et al, 2003;Morrison et al, 1987;Fabricus et al, 2013;Freeman et al, 2008;de Brabander et al, 1998;Jacobs et al, 1997;Flood, 1991;Flood et al, 1985;Scheff et al, 2001;Freire-Cobo et al, 2021;Edler et al, 2020 (Continues) Pike et al, 1995;Vehmas et al, 2003;Serrano-Pozo, Mielke, et al, 2011;Wong, 2013;Striet et al, 2004;Lopes et al, 2008;Damani et al, 2011;…”

Section: F I G U R Ementioning

confidence: 99%

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Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies

August

Semendeferi

Marchetto

2022

J of Comparative Neurology

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that is ultimately fatal. Currently, millions of Americans are living with AD, and this number is predicted to grow with increases in the aging population. Interestingly, despite the prevalence of AD in human populations, the full AD phenotype has not been observed in any nonhuman primate (NHP) species, and it has been suggested that NHPs are immune to neurodegenerative diseases such as AD.Here, we review the typical age-related changes and pathologies in humans along with the neuropathologic changes associated with AD, and we place this information in the context of the comparative neuropathology of NHPs. We further propose the use of induced pluripotent stem cell technology as a way of addressing initial molecular processes and changes that occur in neurons and glia (in both humans and NHPs) when exposed to AD-inducing pathology prior to cell death. K E Y W O R D Sstem cells, brain aging, alzheimer's disease, primate 1 2 OVERVIEW OF AD IN HUMANSAD is the most common neurodegenerative disorder seen in agedependent dementia, and its prevalence is rapidly increasing. Two main 2940

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Section: Brain Aging In Humans and Nonhuman Primatesmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies

August

Semendeferi

Marchetto

2022

J of Comparative Neurology

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“…Other approaches using mouse chimeric models with human IPSC cells [ 35 ], non-human primates, especially marmosets [ 36 ] and sophisticated transgene mouse models based on late-onset AD genes [ 37 ] do reflect the complex interaction of many processes involved and bridge some of the translational gap, but are notoriously low-throughput and have limited capacity.…”

Section: Strategies For Selecting Best Combinationsmentioning

confidence: 99%

Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer’s Disease

Geerts¹,

Graaf²

2021

ADR

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With the approval of aducanumab on the “Accelerated Approval Pathway” and the recognition of amyloid load as a surrogate marker, new successful therapeutic approaches will be driven by combination therapy as was the case in oncology after the launch of immune checkpoint inhibitors. However, the sheer number of therapeutic combinations substantially complicates the search for optimal combinations. Data-driven approaches based on large databases or electronic health records can identify optimal combinations and often using artificial intelligence or machine learning to crunch through many possible combinations but are limited to the pharmacology of existing marketed drugs and are highly dependent upon the quality of the training sets. Knowledge-driven in silico modeling approaches use multi-scale biophysically realistic models of neuroanatomy, physiology, and pathology and can be personalized with individual patient comedications, disease state, and genotypes to create ‘virtual twin patients’. Such models simulate effects on action potential dynamics of anatomically informed neuronal circuits driving functional clinical readouts. Informed by data-driven approaches this knowledge-driven modeling could systematically and quantitatively simulate all possible target combinations for a maximal synergistic effect on a clinically relevant functional outcome. This approach seamlessly integrates pharmacokinetic modeling of different therapeutic modalities. A crucial requirement to constrain the parameters is the access to preferably anonymized individual patient data from completed clinical trials with various selective compounds. We believe that the combination of data- and knowledge driven modeling could be a game changer to find a cure for this devastating disease that affects the most complex organ of the universe.

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“…In line with this scenario, most therapeutic trials based on findings from rodent NDs models have failed clinically [8] . NHPs are closer to humans than other species of animals, especially in their brain structure and function, as well as the aging process [9,10] . Recently, several NHP ND models have been generated and provided new insights into ND pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Modeling neurodegenerative diseases using non-human primates: advances and challenges

Li¹,

He²,

Li³

et al. 2022

Ageing Neur Dis

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Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are pathologically characterized by progressive loss of selective populations of neurons in the affected brain regions and clinically manifested by cognitive, motor, and psychological dysfunctions. Since aging is the major risk factor for NDs and the elderly population is expected to expand considerably in the coming decades, the prevalence of NDs will significantly increase, leading to a greater medical burden to society and affected families. Despite extensive research on NDs, no effective therapy is available for NDs, largely due to a lack of complete understanding of the pathogenesis of NDs. Although research on small animal and rodent models has provided tremendous knowledge of molecular mechanisms of disease pathogenesis, few translational successes have been reported in clinical trials. In particular, most genetically modified rodent models are unable to recapitulate striking and overt neurodegeneration seen in the patient brains. Non-human primates (NHPs) are the most relevant laboratory animals to humans, and recent studies using NHP neurodegeneration models have uncovered important pathological features of NDs. Here, we review the unique features of NHPs for modeling NDs and new insights into AD, PD, and ALS gained from animal models, highlight the contribution of gene editing techniques to establishing NHP models, and discuss the challenges of investigating NHP models.

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Comparative neuropathology in aging primates: A perspective

Cited by 17 publications

References 260 publications

Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies

Brain aging, Alzheimer's disease, and the role of stem cells in primate comparative studies

Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer’s Disease

Modeling neurodegenerative diseases using non-human primates: advances and challenges

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