Animal models of cerebral amyloid angiopathy

Jäkel, Lieke; Nostrand, William E. Van; Nicoll, James A. R.; Werring, David J.; Verbeek, Marcel M.

doi:10.1042/cs20170033

Cited by 47 publications

(62 citation statements)

References 192 publications

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“…49 Although naturally occurring models of CAA exist, most notably in canines and nonhuman primates, the experimental use of these species for large cohort experimentation and testing is limited because of the cost and time needed for CAA to develop (decade or decades). 50 Thus, there is a need for a better experimental model of CAA. The use of rats, specifically transgenic rats, to investigate the pathogenesis of human central nervous system disorders offers several distinct advantages over transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Davis

Hatfield

et al. 2018

The American Journal of Pathology

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105

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Accumulation of fibrillar amyloid b protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid b protein in brain and faithfully recapitulates many of the pathologic aspects of human smallvessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. (Am J Pathol 2018, 188: 2877e2889; https://doi.

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Section: Discussionmentioning

confidence: 99%

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Davis

Hatfield

et al. 2018

The American Journal of Pathology

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105

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“…Similar to this study, our populations of dogs with microhemorrhages were primarily small-breed dogs; because we selected our controls to be as similar in age as possible to the dogs with cognitive dysfunction or microhemorrhages, we cannot comment on the effect of age, although all of our dogs were older (>9 years). It is also possible that smaller breeds would be expected to predominate because they live long enough to develop degenerative brain disease, compared with larger dog breeds Both cerebral amyloid angiopathy and cognitive dysfunction are well-established pathologies of elderly dogs (Uchida, Nakayama & Goto, 1991;Shimada et al, 1992;Wegiel et al, 1995;Yoshino et al, 1996;Colle et al, 2000;Jakel et al, 2017;Rodrigues et al, 2018;Hasegawa et al, 2005;Noh et al, 2017;Landsberg, Nichol & Araujo, 2012;Dewey et al, 2019;Dewey, 2016;Schutt, Toft & Berendt, 2015). Our study suggests that the dogs with spontaneous brain microhemorrhages represent a distinct neurodegenerative brain disorder with some similarities to cognitive dysfunction, but other features more reminiscent of cerebral amyloid angiopathy.…”

Section: Discussionmentioning

confidence: 79%

“…Although there is some variability in the literature concerning what constitutes a microhemorrhage, most reports include lesions that are less than 5.0 mm in diameter (Jouvent, Puy & Chabriat, 2016;Ungvari et al, 2017;Murao, Rossi & Cordonnier, 2013;Bos et al, 2018;Sharma et al, 2018). Pathologists have identified both cerebral amyloid angiopathy and cerebral microbleeds in geriatric dogs (Uchida, Nakayama & Goto, 1991;Shimada et al, 1992;Wegiel et al, 1995;Yoshino et al, 1996;Colle et al, 2000;Jakel et al, 2017;Rodrigues et al, 2018), and clinicians have described putative microhemorrhages in geriatric dogs undergoing MRI (Fulkerson et al, 2012;Hodshon, Hecht & Thomas, 2014;Kerwin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Interthalamic adhesion size in aging dogs with presumptive spontaneous brain microhemorrhages: a comparative retrospective MRI study of dogs with and without evidence of canine cognitive dysfunction

Dewey

Rishniw

Johnson

et al. 2020

PeerJ

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Objective Spontaneous brain microhemorrhages in elderly people are present to some degree in Alzheimer’s disease patients but have been linked to brain atrophy in the absence of obvious cognitive decline. Brain microhemorrhages have recently been described in older dogs, but it is unclear whether these are associated with brain atrophy. Diminution of interthalamic adhesion size-as measured on MRI or CT-has been shown to be a reliable indicator of brain atrophy in dogs with canine cognitive dysfunction (CCD) in comparison with successfully aging dogs. We hypothesized that aging dogs with brain microhemorrhages presenting for neurologic dysfunction but without obvious features of cognitive decline would have small interthalamic adhesion measurements, like dogs with CCD, compared with control dogs. The objective of this study was to compare interthalamic adhesion size between three groups of aging (>9 years) dogs: (1) neurologically impaired dogs with presumptive spontaneous brain microhemorrhages and no clinical evidence of cognitive dysfunction (2) dogs with CCD (3) dogs without clinical evidence of encephalopathy on neurologic examination (control dogs). MR images from 52 aging dogs were reviewed and measurements were obtained of interthalamic adhesion height (thickness) and mid-sagittal interthalamic adhesion area for all dogs, in addition to total brain volume. Interthalamic adhesion measurements, either absolute or normalized to total brain volume were compared between groups. Signalment (age, breed, sex), body weight, presence and number of SBMs, as well as other abnormal MRI findings were recorded for all dogs. Results All interthalamic adhesion measurement parameters were significantly (P < 0.05) different between control dogs and affected dogs. Both dogs with cognitive dysfunction (12/15; 80%) and dogs with isolated brain microhemorrhages had more microhemorrhages than control dogs (3/25; 12%). Affected dogs without cognitive dysfunction had significantly more microhemorrhages than dogs with cognitive dysfunction. In addition to signs of cognitive impairment for the CCD group, main clinical complaints for SBM and CCD dogs were referable to central vestibular dysfunction, recent-onset seizure activity, or both. Geriatric dogs with spontaneous brain microhemorrhages without cognitive dysfunction have similar MRI abnormalities as dogs with cognitive dysfunction but may represent a distinct disease category.

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“…Saimiri boliviensis boliviensis (SQMs) were utilized in the present study due to their unique characteristic of naturally occurring amyloid-related pathology. An important feature of Aβ depositions in SQMs is their species-specific propensity to CAA (Elfenbein et al, 2007;Heuer et al, 2012Heuer et al, , 2017Rosen et al, 2016;Jäkel et al, 2017;Devinsky et al, 2018). CAA is almost universally present in AD.…”

Section: Discussionmentioning

confidence: 99%

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

Nehete

Williams

Chitta

et al. 2020

Front. Aging Neurosci.

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One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.

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Animal models of cerebral amyloid angiopathy

Cited by 47 publications

References 192 publications

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Interthalamic adhesion size in aging dogs with presumptive spontaneous brain microhemorrhages: a comparative retrospective MRI study of dogs with and without evidence of canine cognitive dysfunction

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

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