Deposition of phosphorylated amyloid‐β in brains of aged nonhuman primates and canines

Kumar, Sathish; Frost, Jeffrey L.; Cotman, Carl W.; Head, Elizabeth; Palmour, Roberta M.; Lemere, Cynthia A.; Walter, Jochen

doi:10.1111/bpa.12573

Cited by 9 publications

(16 citation statements)

References 13 publications

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“…Immunohistochemistry was performed on 8-10 μm thick sections of hippocampus and cortex as previously described [20,41], using three different primary antibodies. In brief, human brain sections were deparaffinized in two changes of Histo-Clear (National Diagnostics, Atlanta, GA) and rehydrated in graded ethanol solutions.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…We recently showed that Aβ undergoes phosphorylation at serine residue 8, which affects its conformation, aggregation, neurotoxicity and proteolytic degradation [18,25,27,37,38]. Phosphorylated Ser8-Aβ (pSer8Aβ) occurs in vivo in the brains of human AD patients, nonhuman primates and canines [39][40][41][42]. Notably, the detection of pSer8Aβ, together with pyroglutamate modified Aβ in brain sections or brain extracts has recently been explored to establish a staging system for AD pathology based on the sequential deposition of these modified Aβ variants during the pathogenesis of AD [42].…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Kumar

Lemere

Walter

2020

acta neuropathol commun

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The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct agedependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

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Section: Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Kumar

Lemere

Walter

2020

acta neuropathol commun

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“…Most old NHP species present different degrees of amyloidosis in areas important for cognition, like the neocortex and hippocampus (Table 1). Extracellular plaques and vascular amyloid deposits have been detected in the brains of old orangutans, gorillas, and chimpanzees (Edler et al, 2017; Gearing et al, 1997; Kimura et al, 2001; Perez et al, 2013; Rosen et al, 2016) and also in cercopithecids like macaques (Geula et al, 2002; Kodama et al, 2010; Oikawa et al, 2010; Podlisny et al, 1991; Rosen et al, 2016; Uchihara et al, 2016), baboons (Ndung'u et al, 2012; Schultz, Hubbard, et al, 2000), and vervets (Kumar et al, 2018; Latimer et al, 2019). In ceboids, amyloidosis is described for marmosets (Geula et al, 2002; Rodriguez‐Callejas et al, 2016), squirrel monkeys (Elfenbein et al, 2007; Walker et al, 1990), and cotton‐top tamarins (Lemere et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…However, guanidine‐extracted insoluble Aβ 42 and Aβ 40 levels in temporal and parietal cortices of old vervets (19.5–23.4 year old, n = 9) were significantly higher than those of middle‐aged vervets (8.2–13.5 year old, n = 9) (Latimer et al, 2019). Also, older animals (>15 years of age) had higher amyloid deposition of both phosphorylated (p‐S8) and nonphosphorylated Aβ variants in the frontal and temporal cortex (Kumar et al, 2018). Generally, no significant age‐related changes were observed in the hippocampus or the visual cortex (Cramer et al, 2018), basal ganglia, brainstem, or cerebellum (Latimer et al, 2019).…”

Section: Cercopithecidsmentioning

confidence: 99%

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Comparative neuropathology in aging primates: A perspective

Freire-Cobo

Edler

Varghese

et al. 2021

American J Primatol

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While humans exhibit a significant degree of neuropathological changes associated with deficits in cognitive and memory functions during aging, non-human primates (NHP) present with more variable expressions of pathological alterations among individuals and species. As such, NHP with long life expectancy in captivity offer an opportunity to study brain senescence in the absence of the typical cellular pathology caused by age-related neurodegenerative illnesses commonly seen in humans. Age-related changes at neuronal population, single cell, and synaptic levels have been well documented in macaques and marmosets, while age-related and Alzheimer's disease-like neuropathology has been characterized in additional species including lemurs as well as great apes. We present a comparative overview of existing neuropathologic observations across the primate order, including classic agerelated changes such as cell loss, amyloid deposition, amyloid angiopathy, and tau accumulation. We also review existing cellular and ultrastructural data on neuronal changes, such as dendritic attrition and spine alterations, synaptic loss and pathology, and axonal and myelin pathology, and discuss their repercussions on cellular and systems function and cognition.

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Naturally occurring histological findings and Alzheimer's‐like pathology in the brain of aging African green monkeys (Chlorocebus sabaeus)

Corey

Illanes

Lawrence

et al. 2023

J of Comparative Neurology

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Nonhuman primates (NHPs) are important to study the pathophysiology of neurodegenerative disease and evaluate therapies targeting the central nervous system (CNS). Understanding the age-associated incidence of natural CNS pathology in a given NHP species is critical to assess the safety of potential treatments for neurodegenerative disorders like Alzheimer's disease (AD). We describe background and age-related neuropathology in the St. Kitts African green monkey (AGM), a recognized translational model for neurodegenerative research, additionally defining the age progression of AD-associated neuropathology in this species. Seventy-one AGM brains were examined, representing age groups of 3-6 years (n = 20), 7-9 years (n = 20), 10-15 years (n = 20), and >15 years (n = 11). A subset of brains (n = 31) was assessed immunohistochemically for AD-related pathology, including expressions of Aβ, tau, and GFAP. Age-related microscopic findings included hemosiderosis, spheroid formation, neuronal lipofuscinosis and neuromelanosis, white matter and neuropil vacuolation, astrocytosis, and focal microgliosis. Non-age-related findings included perivascular ceroid-laden macrophages, meningeal melanosis, and vascular mineralization. Immunohistochemistry revealed 4G8-immunopositive Aβ plaques and vascular deposits in the prefrontal, frontal, cingulate, and temporal cortices of nine animals over 15 years of age, with associated increase in GFAP expression. In 12 animals, 11 over the age of 10 years, phosphorylated tau CP13-immunoreactive neurons, neuropil, and oligodendrocyte-like cells were seen in the prefrontal, frontal, cingulate, orbital, temporal, and entorhinal cortices as well as the hippocampus; no neurofibrillary tangles were observed. AD-related pathology showed an age-related development in cognitive-associated areas in the AGM, highlighting the value of the AGM as a natural model for these neurodegenerative diseases.

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Deposition of phosphorylated amyloid‐β in brains of aged nonhuman primates and canines

Cited by 9 publications

References 13 publications

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Comparative neuropathology in aging primates: A perspective

Naturally occurring histological findings and Alzheimer's‐like pathology in the brain of aging African green monkeys (Chlorocebus sabaeus)

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