Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain

Aluminium (Al) is a neurotoxic metal and Al exposure may be a factor in the aetiology of various neurodegenerative diseases such as Alzheimer's disease (AD). The major pathohistological findings in the AD brain are the presence of neuritic plaques containing beta-amyloid (Abeta) which may interfere with neuronal communication. Moreover, it has been observed that GRP78, a stress-response protein induced by conditions that adversely affect endoplasmic reticulum (ER) function, is reduced in the brain of AD patients. In this study, we investigated the correlation between the expression of Abeta and GRP78 in the brain cortex of mice chronically treated with aluminium sulphate. Chronic exposure over 12 months to aluminium sulphate in drinking water resulted in deposition of Abeta similar to that seen in congophilic amyloid angiopathy (CAA) in humans and a reduction in neuronal expression of GRP78 similar to what has previously been observed in Alzheimer's disease. So, we hypothesise that chronic Al administration is responsible for oxidative cell damage that interferes with ER functions inducing Abeta accumulation and neurodegenerative damage.     

Postnatal changes of IgG and IgM levels in squirrel monkeys (Saimiri sciureus)

Serum IgG and IgM levels were measured in domestically bred squirrel monkeys (Saimiri sciureus) ranging in age from 0 days to 42 months, as well as in adult squirrel monkeys from the wild estimated to be 60 months or older. The results indicated that the transplacental transfer of IgG occurs in the squirrel monkey but the transferability is lower in the squirrel monkey than in the cynomolgus monkey. Immune response in the squirrel monkey occurs just after birth, as shown by IgM production.     

Pleistocene diversification of living squirrel monkeys (Saimiri spp.) inferred from complete mitochondrial genome sequences

In order to enhance our understanding of the evolutionary history of squirrel monkeys (Saimiri spp.), we newly sequenced and analyzed data from seven complete mitochondrial genomes representing six squirrel monkey taxa. While previous studies have lent insights into the taxonomy and phylogeny of the genus, phylogenetic relationships and divergence date estimates among major squirrel monkey clades remain unclear. Using maximum likelihood and Bayesian procedures, we inferred a highly resolved phylogenetic tree with strong support for a sister relationship between Saimiri boliviensis and all other Saimiri, for monophyly of Saimiri oerstedii and Saimiri sciureus sciureus, and for Saimiri sciureus macrodon as the sister lineage to the S. oerstedii/S. s. sciureus clade. We inferred that crown lineages for extant squirrel monkeys diverged around 1.5 million years ago (MYA) in the Pleistocene Epoch, with other major clades diverging between 0.9 and 1.1 MYA. Our results suggest a relatively recent timeline of squirrel monkey evolution and challenge previous conceptions about the diversification of the genus and its expansion into Central America.     

Visual sensitivity in the squirrel monkey

Several indices of visual sensitivity have been obtained from behavioral experiments conducted on the squirrel monkey (Saimiri sciureus). In this species, the photopic spectral sensitivity functions determined by increment-threshold and flicker discrimination procedures are substantially different; the involvement of two different neural processes in the two tasks is suggested. When tested similarly, the thresholds for rod and cone-based vision are not substantially different for squirrel monkeys and humans; however, above cone threshold, for a 500 nm test light, increment threshold is some 0.3 to 0.4 log₁₀ units higher for the squirrel monkey. Rod saturation has also been demonstrated to occur in the squirrel monkey.     

Inhibition of familial cerebral amyloid angiopathy mutant amyloid beta-protein fibril assembly by myelin basic protein

Deposition of fibrillar amyloid beta-protein (Abeta) in the brain is a prominent pathological feature of Alzheimer disease and related disorders, including familial forms of cerebral amyloid angiopathy (CAA). Mutant forms of Abeta, including Dutch- and Iowa-type Abeta, which are responsible for familial CAA, deposit primarily as fibrillar amyloid along the cerebral vasculature and are either absent or present only as diffuse non-fibrillar plaques in the brain parenchyma. Despite the lack of parenchymal fibril formation in vivo, these CAA mutant Abeta peptides exhibit a markedly increased rate and extent of fibril formation in vitro compared with wild-type Abeta. Based on these conflicting observations, we sought to determine whether brain parenchymal factors that selectively interact with and modulate CAA mutant Abeta fibril assembly exist. Using a combination of immunoaffinity chromatography and mass spectrometry, we identified myelin basic protein (MBP) as a prominent brain parenchymal factor that preferentially binds to CAA mutant Abeta compared with wild-type Abeta. Surface plasmon resonance measurements confirmed that MBP bound more tightly to Dutch/Iowa CAA double mutant Abeta than to wild-type Abeta. Using a combination of biochemical and ultrastructural techniques, we found that MBP inhibited the fibril assembly of CAA mutant Abeta. Together, these findings suggest a possible role for MBP in regulating parenchymal fibrillar Abeta deposition in familial CAA.     

Cortisol metabolism in the Bolivian squirrel monkey (Saimiri boliviensis boliviensis)

New World squirrel monkeys (Saimiri spp.) have high circulating cortisol levels but normal electrolytes and blood pressures. The goal of the present study was to gain insight into adaptive mechanisms used by Bolivian squirrel monkeys to minimize the effects of high cortisol on mineralocorticoid receptor (MR) activity and electrolyte and water balance. Aldosterone levels in serum from 10 squirrel monkeys were 17.7 +/- 3.4 ng/dl (normal range in humans, 4 to 31 ng/dl), suggesting that squirrel monkeys do not exhibit a compensatory increase in aldosterone. The squirrel monkey MR was cloned and expressed in COS-7 cells and found to have similar responsiveness to cortisol and aldosterone as human MR, suggesting that squirrel monkey MR is not inherently less responsive to cortisol. To determine whether altered metabolism of cortisol might contribute to MR protection in squirrel monkeys, serum and urinary cortisol and cortisone were measured, and a comprehensive urinary corticosteroid metabolite profile was performed in samples from anesthetized and awake squirrel monkeys. The levels of cortisone exceeded those of cortisol in serum and urine, suggesting increased peripheral 11beta-hydroxysteroid dehydrogenase 2 activity in squirrel monkeys. In addition, a significant fraction (approximately 20%) of total corticosteroids excreted in the urine of squirrel monkeys appeared as 6beta-hydroxycortisol, compared with that in man (1%). Therefore, changes in cortisol metabolism likely contribute to adaptive mechanisms used by Bolivian squirrel monkeys to minimize effects of high cortisol.     

Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of beta-amyloid (Abeta) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathological basis of which is largely unknown. We hypothesized that the accumulation of ISF in dilated periarterial spaces of the WM in AD correlates with the severity of CAA, with the total Abeta load in the cortex and with Apo E genotype. A total of 24 AD brains and 17 nondemented age-matched control brains were examined. CAA was seen in vessels isolated from brain by using EDTA-SDS lysis stained by Thioflavin-S. Total Abeta in gray matter and WM was quantified by immunoassay, ApoE genotyping by PCR, and dilatation of perivascular spaces in the WM was assessed by quantitative histology. The study showed that the frequency and severity of dilatation of perivascular spaces in the WM in AD were significantly greater than in controls (P< 0.001) and correlated with Abeta load in the cortex, with the severity of CAA, and with ApoE epsilon4 genotype. The results of this study suggest that dilation of perivascular spaces and failure of drainage of ISF from the WM in AD may be associated with the deposition of Abeta in the perivascular fluid drainage pathways of cortical and leptomeningeal arteries. This failure of fluid drainage has implications for therapeutic strategies to treat Alzheimer's disease.     

Studies of the Sal I strain of Plasmodium vivax in the squirrel monkey (Saimiri sciureus)

The Sal I strain of Plasmodium vivax was successfully adapted to three phenotypes of the squirrel monkey, Saimiri sciureus. Through five linear blood passages, parasitemias in excess of 200,000/mm3 blood were attained; Bolivian phenotype Saimiri appear to develop higher peak parasitemias. Sporozoites of the Sal I strain inoculated intravenously produced patent parasitemias in all five squirrel monkeys challenged, with prepatent periods ranging from 21 to 38 days. Anopheles freeborni and An. gambiae were the most susceptible of eight anopheline species fed on infected squirrel monkeys. As a model for in vivo studies of P. vivax the Sal I strain in Saimiri has great potential.     

Androgen resistance in squirrel monkeys (Saimiri spp.)

The goal of this study was to understand the basis for high androgen levels in squirrel monkeys (Saimiri spp.). Mass spectrometry was used to analyze serum testosterone, androstenedione, and dihydrotestosterone of male squirrel monkeys during the nonbreeding (n = 7) and breeding (n = 10) seasons. All hormone levels were elevated compared with those of humans, even during the nonbreeding season; the highest levels occurred during the breeding season. The ratio of testosterone to dihydrotestosterone in squirrel monkeys is high during the breeding season compared to man. Squirrel monkeys may have high testosterone to compensate for inefficient metabolism to dihydrotestosterone. We also investigated whether squirrel monkeys have high androgens to compensate for low-activity androgen receptors (AR). The response to dihydrotestosterone in squirrel monkey cells transfected with AR and AR-responsive reporter plasmids was 4-fold, compared with 28-fold in human cells. This result was not due to overexpression of cellular FKBP51, which causes glucocorticoid and progestin resistance in squirrel monkeys, because overexpression of FKBP51 had no effect on dihydrotestosterone-stimulated reporter activity in a human fibroblast cell line. To test whether the inherently low levels of FKBP52 in squirrel monkeys contribute to androgen insensitivity, squirrel monkey cells were transfected with an AR expression plasmid, an AR-responsive reporter plasmid, and a plasmid expressing FKBP52. Expression of FKBP52 decreased the EC50 or increased the maximal response to dihydrotestosterone. Therefore, the high androgen levels in squirrel monkeys likely compensate for their relatively low 5 alpha-reductase activity during the breeding season and AR insensitivity resulting from low cellular levels of FKBP52.     

Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology

Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-beta peptide (Abeta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-beta and downstream Smad2/3 signaling (TGF-beta-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-beta receptor type II in C57BL/6 mice (CD11c-DNR), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular beta-amyloid deposits and Abeta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of Abeta-containing peripheral macrophages around cerebral vessels and beta-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-beta-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased Abeta phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-beta receptor. Taken together, our results suggest that blockade of TGF-beta-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.     

Predation by squirrel monkeys and double-toothed kites on tent-making bats

Central American squirrel monkeys (Saimiri oerstedi) appear to recognize the modified leaves that phyllostomid bats utilize for diurnal roost sites. The monkeys visually and manually search these bat tents for both bats and insects. Adult males are the most successful at capturing bats. Nonvolant juvenile bats are more vulnerable to monkey predation than are adults. Bats that escape monkey predation frequently are captured by doubletoothed kites (Harpagus bidentatus) that tend foraging troops of monkeys. Predation by squirrel monkeys, coupled with that of double-toothed kites, may be a significant source of mortality for tent-making bats.     

The role of complement in Alzheimer's disease pathology

Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review will examine the origins of complement in the brain and the role of beta-amyloid peptide (Abeta) in complement activation in Alzheimer's disease, an event that might serve as a nidus of chronic inflammation. Pharmacology therapies that may serve to inhibit Abeta-mediated complement activation will also be discussed.     

Genetically determined antigens of squirrel monkey (Saimiri sciureus) IgG

Alloantigens of squirrel monkey (Saimiri sciureus) IgG were studied using alloantisera prepared by cross-immunizations among four subspecies. The results demonstrated the occurrence of IgG antigenic polymorphism. Three distinct Fd fragment allotypes were detected. Greater alloantigenic complexity occurred among Colombian and Peruvian squirrel monkeys, which occupy the more central regions of the geographic range; Bolivian and Guyanan monkeys, which occupy the extremes of the range, expressed less alloantigenic complexity.     

Metal chelator decreases Alzheimer beta-amyloid plaques.

Transgenic mice developing beta-amyloid (Abeta) plaques are advancing experimental treatment strategies for Alzheimer's disease. The metal chelator, clioquinol, is reported by Cherny et al. (2001) to reduce Abeta plaques, presumably by chelation of Abeta-associated zinc and copper. This and other recent Abeta-modulating treatment approaches are discussed.     

Disparate Data Sets Resolve Squirrel Monkey (Saimiri) Taxonomy: Implications for Behavioral Ecology and Biomedical Usage

Squirrel monkeys (Saimiri spp.) are the most commonly used neotropical (platyrrhine) monkeys in biomedical research; however, no consensus exists as to the phylogenetic relationships amongst geographic variants or whether these variants represent species or subspecies. Here we report a strongly supported squirrel monkey phylogeny, congruent across multiple data sets, including new field data and the first molecular (mtDNA) cladogram. These data support species-level classification for the three major groups in this study. Approximately the same amount of molecular divergence exists among Saimiri oerstedii, S. sciureus, and S. boliviensis. The S. sciureus/S. oerstedii ancestor diverged from S. boliviensis and shortly thereafter S. sciureus and S. oerstedii diverged. Until now, lack of a robust taxonomy has hindered exploitation of the massive potential of Saimiri for comparative studies. No other primate genus displays such widely divergent, genetically-based social behaviors. Our taxonomy also provides robust support for previous warnings against the widespread use of hybrid squirrel monkeys as research models.     

Increased production of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney microsomes of squirrel monkeys (Saimiri spp.)

In squirrel monkeys (Saimiri spp.), cortisol circulates at levels much higher than those seen in man and other Old World primates, but squirrel monkeys exhibit no physiologic signs of the mineralocorticoid effects of cortisol. These observations suggest that squirrel monkeys have mechanisms for protection of the mineralocorticoid receptor (MR) from these high levels of cortisol. We previously showed that the serum cortisol to cortisone ratio in these animals is low relative to that in human serum, suggesting that production of the MR protective enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), is increased in squirrel monkeys. Here, we directly evaluate whether increased production of 11beta-HSD2, which inactivates cortisol to cortisone, is a mechanism for protection of MR. In vitro assays showed that 11beta-HSD2 activity in squirrel monkey kidney microsomes was 3 to 7 times higher than that seen in kidney microsomes from pig or rabbit. 11beta-HSD2 protein detected by Western blot analysis was 4 to 9 times greater in squirrel monkey microsomes than in pig or rabbit microsomes. Comparison of the effect of expression of either human or squirrel monkey 11beta-HSD2 on MR transactivation activity showed similar inhibition of MR response to cortisol by both enzymes, indicating that the intrinsic activities of the human and squirrel monkey enzymes are similar. These findings suggest that one mechanism by which squirrel monkeys protect the MR from activation by high cortisol levels in the kidney is by upregulation of 11beta-HSD2 activity through increased production of the enzyme.     

Squirrel monkeys support replication of BK virus more efficiently than simian virus 40: an animal model for human BK virus infection

We performed experiments to test the suitability of squirrel monkeys (Saimiri sciureus) as an experimental model for BK virus (BKV) and simian virus 40 (SV40) infection. Four squirrel monkeys received intravenous inoculation with BKV Gardner strain, and six squirrel monkeys received intravenous inoculation with SV40 777 strain. Eight of 10 monkeys received immunosuppression therapy, namely, cyclophosphamide subcutaneously either before or both before and after viral inoculation. The presence of viral infection was assessed by quantitative real-time PCR amplification of viral DNA from blood, urine, and 10 tissues. We found that squirrel monkeys were susceptible to infection with BKV, with high viral copy number detected in blood and viral genome detected in all tissues examined. BKV genome was detected in urine from only one monkey, while three monkeys manifested focal interstitial nephritis. BKV T antigen was expressed in renal peritubular capillary endothelial cells. By contrast, SV40 was detected at very low copy numbers in only a few tissues and was not detected in blood. We conclude that the squirrel monkey is a suitable animal for studies of experimental BKV infection and may facilitate studies of viral entry, pathogenesis, and therapy.     

Age-related changes of Alzheimer's disease-associated proteins in cynomolgus monkey brains

We characterized senile plaques (SPs) immunohistochemically in cynomolgus monkey brains and also examined age-related biochemical changes of Alzheimer's disease (AD)-associated proteins in these brains from monkeys of various ages. In the neocortex of aged monkeys (>20 years old), we found SPs but no neurofibrillary tangles (NFTs). Antibodies against beta-amyloid precursor protein (APP) or apolipoprotein E (ApoE) stained SPs; however, the pattern of immunostaining was different for the two antigens. APP was present only in swollen neurites, but ApoE was present throughout all parts of SPs. Western blot analysis revealed that the pattern of APP expression changed with age. Although full-length APP695 protein was mainly expressed in brains from young monkeys (4-years-old), the expression of full-length APP751 protein was increased in brains from older monkeys (>20 years old). Biochemical analyses also showed that levels of various AD-associated proteins increased significantly with age in nerve ending fractions. Both SP-associated (APP) and NFT-associated proteins (tau, activated glycogen synthase kinase 3beta, cyclin dependent kinase 5, p35, and p25) accumulated in the nerve ending fraction with increasing age; however, we found no NFTs or paired helical filaments of tau in aged cynomolgus monkey brains. This age-related accumulation of these proteins in the nerve ending fraction was similar to that observed in our laboratory previously for presenilin-1 (PS-1). The accumulation of these SP-associated proteins in this fraction may be a causal event in the spontaneous formation of SPs; thus, SPs may be formed initially in nerve endings. Taken together, these results suggest that intensive investigation of age-related changes in the nerve ending and in axonal transport will contribute to a better understanding of the pathogenesis of neurodegenerative disorders such as AD.     

TISSUE DISTRIBUTION AND METABOLISM OF THE LATHYRUS SATIVUS NEUROTOXIN, L-3-OXALYLAMINO-2-AMINOPROPIONIC ACID, IN THE SQUIRREL MONKEY

Abstract– Although the L. sativus neurotoxin, L-3-oxalylamino-2-aminopropionic acid, is believed to cause neurological disease in humans, evidence that the toxin can enter the central nervous system except in animals with an immature or damaged blood-brain barrier is lacking. Experiments described here suggest that an intraperitoneal dose of L-3-[¹⁴C-oxalyl]amino-2-aminopropionic acid enters the central nervous system of young squirrel monkeys ( Saimiri sciureus ) whose blood-brain barrier is mature. Most of the radioactivity recovered from monkey urine and tissues 1 h after injection was unchanged toxin. None was recovered in expired air as radioactive carbon dioxide.     

Integration of field and captive studies for understanding the behavioral ecology of the squirrel monkey (Saimiri sp.)

Captive and field studies both provide valuable and complementary information that lead to a better understanding of a species' behavioral ecology. Here, we review studies from wild, captive, and semi-free ranging populations of squirrel monkeys (Saimiri sp.), in order to (a) provide a more current (1985-2010) review of Saimiri behavioral ecology and (b) illustrate that integrating data collected in a variety of settings is an effective approach to addressing ecological questions in primates. Captive environments, such as zoological facilities and research colonies, can be advantageous to researchers by allowing longitudinal studies of behavior and reproduction, as well as providing opportunities for gathering data on life history, because physiological and life history data are known for individual animals. Studies of field populations can provide contextual information regarding the adaptive nature of behaviors that are studied in captivity. Squirrel monkeys are small, neotropical primates that have extensively been used in captive research. As the last in-depth review of Saimiri biology was published in 1985 [Rosenblum & Coe, The squirrel monkey. New York: Academic Press], we review studies since conducted on Saimiri ecology, life history, social behavior, reproduction, and conservation. Our review indicates that there is much variation in socioecology and life history traits between Saimiri species and, surprisingly, also between populations of the same species studied at different locales. In addition, much is known about squirrel monkey reproductive physiology, basic ecology, and vocal communication, but data are still lacking in the fields of life history and some adaptive components and social behavior. In particular, longitudinal studies in the field would be particularly relevant for a genus with a slow life history such as Saimiri. Finally, few data (captive or wild) are available on S. ustus and S. vanzolinii, though at least one of these species is threatened.