A nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis

Latimer, Caitlin S.; Shively, Carol A.; Keene, C. Dirk; Jorgensen, Matthew J.; Andrews, Rachel N.; Register, Thomas C.; Montine, Thomas J.; Wilson, Angela; Neth, Bryan J.; Mintz, Akiva; Maldjian, Joseph A.; Whitlow, Christopher T.; Kaplan, Jay R.; Craft, Suzanne

doi:10.1016/j.jalz.2018.06.3057

Cited by 77 publications

(116 citation statements)

References 50 publications

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“…Paspalas et al (76) described recently AD-like tau pathology in an aged rhesus monkey, including the presence of NFTs observed using electron microscopy and autophagic vacuoles reflective of neuron death. Others have described the presence of AD-like NFTs in aged African green monkeys (77,78). These Old World anthropoid species are valuable models for tracking ADlike pathology at the biochemical/histochemical level and suggest that the molecular machinery for NFT formation may exist across primate species.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Beckman

Ott

Donis-Cox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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As the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and Alzheimer’s disease (AD) has increased and is projected to cost more than $290 billion in the United States in 2019. Despite significant investment in research over the last decades, there is no effective treatment to prevent or delay AD progression. There is a translational gap in AD research, with promising drugs based on work in rodent models failing in clinical trials. Aging is the leading risk factor for developing AD and understanding neurobiological changes that affect synaptic integrity with aging will help clarify why the aged brain is vulnerable to AD. We describe here the development of a rhesus monkey model of AD using soluble oligomers of the amyloid beta (Aβ) peptide (AβOs). AβOs infused into the monkey brain target a specific population of spines in the prefrontal cortex, induce neuroinflammation, and increase AD biomarkers in the cerebrospinal fluid to similar levels observed in patients with AD. Importantly, AβOs lead to similar dendritic spine loss to that observed in normal aging in monkeys, but so far without detection of amyloid plaques or tau pathology. Understanding the basis of synaptic impairment is the most effective route to early intervention and prevention or postponement of age-related cognitive decline and transition to AD. These initial findings support the use of monkeys as a platform to understand age-related vulnerabilities of the primate brain and may help develop effective disease-modifying therapies for treatment of AD and related dementias.

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Section: Discussionmentioning

confidence: 99%

Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Beckman

Ott

Donis-Cox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In summary, research in monkeys has played, and can continue to play, a vital role in revealing the etiology of LOAD. Although this review has focused on research from aging rhesus monkeys, studies of other primate species, such as African green monkeys (34,96) and marmosets (97), can expand our knowledge of how the aging association cortex becomes vulnerable to LOAD-like pathology. This view can complement existing strategies using canine models (98) and mouse models to produce a more comprehensive understanding of LOAD etiology.…”

Section: Future Directions: Transgenic Monkeysmentioning

confidence: 99%

Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

Arnsten

Datta

Leslie

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Although mouse models of Alzheimer’s disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an “endosomal traffic jam” that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

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“…While substituting the AT8 pTau capture antibody with the AT270 antibody allowed detection of pTau in aged vervets and mutant C. elegans strains, it is possible that additional modifications of the original assay format could still permit Luminex-based quantification of AT8 reactive pTau in those samples. It has been observed that application of NIA-AA guidelines to the analysis of aged vervets identified only 'not' and 'low' AD neuropathologic change [12]. A comprehensive analysis of pTau in the dog brain by immunohistochemistry found marked hyperphosphorylation of Tau in only three out of 24 study dogs, only one of these three dogs was a small dog comparable to the breeds used in our investigation [13].…”

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confidence: 61%

“…While some studies were able to detect AT8-reactive pTau or pTau (Ser396) in dog brains [14,15], others could not detect AT8-reactive pTau in dog brains [16,17]. Similarly, some studies report AT8reactive pTau in aged vervets [12], others detected either no or different pTau epitopes in rhesus monkeys or marmosets [18,19]. It will be of interest to apply our current investigation not only to larger samples, but also to additional species, for example cats [20], that could be used as novel alternative models for the study of AD neuropathologic change.…”

mentioning

confidence: 99%

Cross species application of quantitative neuropathology assays developed for clinical Alzheimer’s disease samples

Urfer

Latimer

Ladiges

et al. 2019

Pathobiology of Aging & Age-related Diseases

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A major obstacle for preclinical testing of Alzheimer's disease (AD) therapies is the availability of translationally relevant AD models. Critical for the validation of such models is the application of the same approaches and techniques used for the neuropathological characterization of AD. Deposition of amyloid-β 42 (Aβ42) plaques and neurofibrillary tangles containing phospho-Tau (pTau) are the pathognomonic features of AD. In the neuropathologic evaluation of AD, immunohistochemistry (IHC) is the current standard method for detection of Aβ42 and pTau. Although IHC is indispensable for determining the distribution of AD pathology, it is of rather limited use for assessment of the quantity of AD pathology. We have recently developed Luminex-based assays for the quantitative assessment of Aβ42 and pTau in AD brains. These assays are based on the same antibodies that are used for the IHC-based diagnosis of AD neuropathologic change. Here we report the application and extension of such quantitative AD neuropathology assays to commonly used genetically engineered AD models and to animals that develop AD neuropathologic change as they age naturally. We believe that identifying AD models that have Aβ42 or pTau levels comparable to those observed in AD will greatly improve the ability to develop AD therapies.Abbreviations: Alzheimer's disease (AD); amyloid β 42 (Aβ42); phospho-Tau (pTau); immunohistochemistry (IHC) ARTICLE HISTORY

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A nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis

Cited by 77 publications

References 50 publications

Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging

Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

Cross species application of quantitative neuropathology assays developed for clinical Alzheimer’s disease samples

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