Conditional expression of human β-hexosaminidase in the neurons of Sandhoff disease rescues mice from neurodegeneration but not neuroinflammation

This study evaluated whether GM(2) ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB(−/−) mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB(−/−) mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB(−/−) mice from GM(2) neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM(2) presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored

Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer’s Disease

Galactic Cosmic Radiation consisting of high-energy, high-charged (HZE) particles poses a significant threat to future astronauts in deep space. Aside from cancer, concerns have been raised about late degenerative risks, including effects on the brain. In this study we examined the effects of $^{56}$Fe particle irradiation in an APP/PS1 mouse model of Alzheimer’s disease (AD). We demonstrated 6 months after exposure to 10 and 100 cGy $^{56}$Fe radiation at 1 GeV/µ, that APP/PS1 mice show decreased cognitive abilities measured by contextual fear conditioning and novel object recognition tests. Furthermore, in male mice we saw acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was further confirmed by ELISA measures of Aβ isoforms. Increases were not due to higher levels of amyloid precursor protein (APP) or increased cleavage as measured by levels of the β C-terminal fragment of APP. Additionally, we saw no change in microglial activation levels judging by CD68 and Iba-1 immunoreactivities in and around Aβ plaques or insulin degrading enzyme, which has been shown to degrade Aβ. However, immunohistochemical analysis of ICAM-1 showed evidence of endothelial activation after 100 cGy irradiation in male mice, suggesting possible alterations in Aβ trafficking through the blood brain barrier as a possible cause of plaque increase. Overall, our results show for the first time that HZE particle radiation can increase Aβ plaque pathology in an APP/PS1 mouse model of AD

Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease

Abstract Neuroinflammation is considered one of the cardinal features of Alzheimer’s disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD

Radiation increases select Aβ isoforms but has no effect on APP processing.

<p>Dot plot analysis of soluble Aβ40 (<i>A</i>), Aβ42 (<i>B</i>) and insoluble Aβ40 (<i>C</i>) and Aβ42 (<i>D</i>). Each dot represents one animal. Data was analyzed with Student’s t-test for the females and one-way ANOVA with a Bonferroni post test for the males. (<i>E, F</i>) Male 0 cGy and 100 cGy APP (<i>E</i>) and β-C terminal fragment (<i>F</i>) protein levels were measured via Western blot and standardized to α-tubulin. Representative images of blots are present in <i>E’</i> and <i>F’</i>. Results were analyzed with Student’s t-test. Data displayed as mean ± SD, <i>n</i> = 8–14 animals per dose. *<i>P<.05, **P<.01</i>.</p

Immunohistochemical staining for Congo red and 6E10 increases after ⁵⁶Fe particle irradiation.

<p>(<i>A, C</i>) Representative images of half male brains stained for Congo red (<i>A</i>) or 6E10 (<i>C</i>) 6 months after 0 cGy or 100 cGy ⁵⁶Fe particle radiation. Scale bar is 1 mm. (<i>B, D</i>) Quantitative measurement of percent plaque area assessed with Congo red (<i>B</i>) and 6E10 (<i>D</i>). In addition, total number of individual 6E10 positive plaques (<i>E</i>) and the average size of plaques (µm²) (<i>F</i>) was determined. Each dot represents a single animal measured as percent area of the cortex and hippocampus combined. Data was analyzed with Student’s t-test for the females and one-way ANOVA with a Bonferroni post test for the males. Data displayed as mean ± SD, <i>n</i> = 8–14 animals per dose. *<i>P<.05, **P<.01</i>.</p