Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese‐exposed non‐human primates

Abstract

Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive, and parkinsonian features. Gene expression profiling in the frontal cortex of Cynomologous macaques receiving 3.3-5.0 mg Mn/kg weekly for 10 months showed that 61 genes were increased and four genes were decreased relative to controls from a total of 6766 genes. Gene changes were associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin-proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport, and inflammation. Amyloid-b (Ab) precursor-like protein 1, a member of the amyloid precursor protein family, was the most highly up-regulated gene. Immunohistochemistry confirmed increased amyloid precursor-like protein 1 protein expression and revealed the presence of diffuse Ab plaques in Mn-exposed frontal cortex. Cortical neurons and white matter fibers from Mn-exposed animals accumulated silver grains indicative of on-going degeneration. Cortical neurons also exhibited nuclear hypertrophy, intracytoplasmic vacuoles, and apoptosis stigmata. p53 immunolabeling was increased in the cytoplasm of neurons and in the nucleus and processes of glial cells in Mn-exposed tissue. In summary, chronic Mn exposure produces a cellular stress response leading to neurodegenerative changes and diffuse Ab plaques in the frontal cortex. These changes may explain the subtle cognitive deficits previously demonstrated in these same animals. Keywords: Alzheimer's disease, amyloid-b, amyloid-b precursor-like protein 1, manganese, neurodegeneration, nonhuman primates, p53. J. Neurochem. (2008) 105, 1948-1959. JOURNAL OF NEUROCHEMISTRY | 2008 | 105 | 1948-1959 doi: 10.1111/j.1471-4159.2008 Klos et al. 2006b) that may persist long after cessation of exposure (Bouchard et al. 2007). An association between environmental exposure to Mn and deficits in measures of intellectual functioning has also been described in children (Takser et al. 2003;Wasserman et al. 2006). It has been suggested that chronic exposure to elevated levels of Mn may alter cognitive domains mediated by the frontal cortex and subcortical structures (Josephs et al. 2005). However, there is relatively little or no information on Mn-induced effects on brain structures outside of the basal ganglia. The present study is part of an on-going multidisciplinary effort to characterize the neurological consequences of chronic exposure to Mn in non-human primates. The monkeys described in this communication have been previously shown to have subtle deficits in cognitive function and fine motor control (Schneider et al. 2006). They exhibit decreased levels of amphetamine-induced dopamine release in the striatum measured by positron emission tomography (Guilarte et al. 2006a) and decreased cerebral cortex N-acetylaspartate/creatine ratio measured by magnetic resonance spectroscopy indicative of neuronal loss or dysfunction (Guilarte et al. 2006b). We now present new evidence that in the frontal cortex of these same animals, Mn exposure produces ...

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

“…APLP1 is localized in the cerebral cortex postsynaptic density of rats and humans and its expression was reported to be increased in synaptic development, suggesting a role in synaptogenesis, or synaptic maturation (51). Increased APLP1 expression and neurodegeneration were found in the frontal cortex of manganese-exposed nonhuman primates (52), which could be a compensatory event. Soluble forms of APLP1 (53) and more interestingly, three APLP1-derived amyloid-beta-like peptides (54), were previously observed in human CSF.…”

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

“…Ultrastructural studies report that reactive astrocytes and microglia surround degenerating neurons and contain increased numbers of large secondary lysosomes, indicative of an active phagocytic process (Bikashvili et al 2001). Additionally, it has been reported that Mn induces astrogliosis in the pre-frontal cortex of exposed Cynomolgus macaques and that activated astrocytes in this model were noted proximal to degenerating neurons that expressed amyloid-β precursor-like protein 1 (Guilarte et al 2008b). Collectively, reports from human cases and animal models of manganism suggest a broad spectrum of neuropathological changes in both neurons and glia not only within the basal ganglia, but also within cortical regions as well, which may help to explain some of the nonmotor symptoms of the disorder.…”

“…Instead, neurofilament subunit genes were downregulated in the striatum and in the substantia nigra. Recent work on non-human primates (Guilarte et al 2008b) detected Mn-induced brain gene expression changes mainly affecting apoptosis, protein folding and degradation, inflammation and axonal/vesicular transport. The most up-regulated gene was APLP1, and diffuse amyloid-β plaques were documented in the frontal cortex of the Mn-treated macaques (Guilarte et al 2008b).…”

“…Recent work on non-human primates (Guilarte et al 2008b) detected Mn-induced brain gene expression changes mainly affecting apoptosis, protein folding and degradation, inflammation and axonal/vesicular transport. The most up-regulated gene was APLP1, and diffuse amyloid-β plaques were documented in the frontal cortex of the Mn-treated macaques (Guilarte et al 2008b). These interesting results could support a link between advanced manganism and dementia, as occasionally reported (Bant and Markesbery 1977).…”

The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability

“…9,10 Additionally, Mn overload in brain may be involved in the etiology of AD, since patients with elevated Mn levels exhibit dementia and typical pathological signs of AD characterized by neuritic plaques and neurofibrillary tangles. 10,11 In animal models, chronic Mn treatment induces upregulation of amyloid-like protein 1 and diffuse amyloid b plaques in the frontal cortex of macaques, 12,13 thus supporting a link between advanced-stage manganism and dementia.…”