Developmental toxicant exposure in a mouse model of Alzheimer’s disease induces differential sex-associated microglial activation and increased susceptibility to amyloid accumulation

Abstract

As the resident macrophage of the central nervous system, microglia are thought to contribute to Alzheimer's disease (AD) pathology through lack of neuroprotection. The role of immune dysfunction in AD may be due to disruption of regulatory signals for the activation of microglia that may occur early in development. We hypothesized that early toxicant exposure would systematically activate microglia, possibly reversing the pathological severity of AD. Offspring of a triple transgenic murine model for AD (3×TgAD) were exposed to a model neurotoxicant, lead acetate, from postnatal days (PND) 5-10. Our results indicated that female mice exposed to Pb had a greater and earlier incidence of amyloid burden within the hippocampus, coinciding with decreased markers of microglial activation at PND 50. Pb-exposed males had increased microglial activation at PND 50, as evidence by CD11b expression and microglial abundance, with no significant increase in amyloid burden at that time. There was greater amyloid burden at PND 90 and 180 in both male and female mice exposed to Pb compared with control. Together, these data suggest that activated microglia are neuroprotective against amyloid accumulation early in AD pathology, and that early exposure to Pb could increase susceptibility to later-life neurodegeneration. Likewise, females may be more susceptible to early-life microglial damage, and, subsequently, AD. Further investigation into the sex biased mechanisms by which microglial activation is altered by an early-life immune insult will provide critical insight into the temporal susceptibility of the developing neuroimmune system and its potential role in AD etiopathology.

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease

“…Recent studies suggest that NLRP1 is highly expressed in females in some pathological states such as nodular melanoma, and may be related to female high-risk diseases (Verma et al, 2012;Wu et al, 2016). However, whether NLRP1 and its downstream signals are expressed with a gender difference in AD has not been elucidated.…”

“…The phenotype of APP/PS1 +/− mice [B6. C3-Tg (APPswe, PSEN1dE9) 85Dbo/J] were identified by genotyping, and were used at 30 weeks of age (n = 40, 20 males and 20 females; Li et al, 2016;vonderEmbse et al, 2017;Agostini et al, 2020). Mice were kept in a 12:12 light-dark cycle at room temperature 22-25 • C with relative humidity 60-80%, and free access to standard laboratory chow and drinking water.…”

“…Studies have indicated that both NLRP1 and NLRP3 inflammasomes are expressed and function in a genderdependent manner in some pathological states (Verma et al, 2012;Wu et al, 2016). Recently, Verma et al found that NLRP1 variant was significantly more common in fair-skinned female patients, however, NLRP3 variant was more common in male patients, which was associated the pathogenesis of nodular melanoma (Verma et al, 2012). This finding suggests that NLRP1 may play a more important role in some female high-risk diseases.…”

Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants

“…This demonstrates that early exposure to pollutants induces effects observable in older animals. Early exposure to lead induced a similar cognitive decline, neuroinflammation [111, 112], A β peptide overproduction [113, 114], and tau hyperphosphorylation [115–118] in both mice and rats. Interestingly, Bihaqi et al [119] observed a cognitive decline in rats only when exposed to lead as pups not as adults.…”

Neurodegeneration, demyelination, and astrogliosis in rat spinal cord by chronic lead treatment

“…Activated microglia are neuroprotective against amyloid accumulation early in Alzheimer disease pathology, and early exposure to Pb could increase susceptibility to later‐life neurodegeneration (vonderEmbse et al, ). It has been found that microglial activity in the spinal cord is higher than in the brain, thus possibly affecting development in spinal cord diseases (Olson, ).…”