The Effect of Early Dietary Intervention on Alzheimer\u27s Disease-Related Pathology and Cognitive Function in Mice

Alzheimer’s disease (AD) is a fatal cognitive disorder with proteinaceous brain deposits, neuroinflammation, cerebrovascular dysfunction, and extensive neuronal loss. AD is a multifactorial disease, and lifestyle factors, including diet, are likely associated with the development of AD pathology. Since obesity and diabetes are recognized as risk factors for AD, it might be predicted that a high fat diet (HFD) would worsen AD pathology. However, modeling HFD-induced obesity in animal models of AD has yielded inconclusive results. Some studies report a deleterious effect of HFD on Aβ accumulation, neuroinflammation, and cognitive function, while others report that HFD worsens memory without affecting AD brain pathology. Moreover, several studies report no major effect of HFD on AD-related phenotypes in mice, while other studies show that HFD might, in fact, be protective. The lack of a clear association between HFD consumption and AD-related pathology and cognitive function in AD mouse models might be explained by experimental variations, including AD mouse model, sex of the animals, composition of the HFD, and timeline of HFD consumption. Our study examined the effect of varying the timeline of HFD or control diet (CON) consumption on AD-related pathology and cognitive function in transgenic Tg6799 AD mice. HFD consumption that started at or before 3 months-of-age, prior to severe AD pathology, had protective effects in AD mice. Specifically, it reduced extracellular beta-amyloid (Aβ) deposition, decreased fibrinogen extravasation from blood vessels into the brain parenchyma, and improved cognitive function. RNAseq analysis revealed that HFD affected the expression of genes in the AD mouse cortex related to the stress response, protein folding, endoplasmic reticulum stress, chaperone-mediated protein folding, and the immune system process in AD mice. However, delaying HFD consumption until 6 months-ofage, when AD pathology is ubiquitous, did not provide neuroprotection in AD mice, as there was no change in cortical Aβ deposition in 11-month-old mice. Surprisingly, despite the delayed onset of HFD consumption, HFD still reduced the extravasation of fibrinogen into the brain. Overall, we demonstrate that the timeline of HFD consumption plays an important role in how dietary fats affect AD-related pathology and cognitive function in a transgenic mouse model of AD

25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner

BACKGROUND: Genome-wide association studies of Alzheimer\u27s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. METHODS: We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. RESULTS: We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. CONCLUSION: 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4\u3e\u3eE2/E3) and thus may be an important mediator of neuroinflammation in AD

Early-Life Stress Does Not Aggravate Spatial Memory or the Process of Hippocampal Neurogenesis in Adult and Middle-Aged APP/PS1 Mice

Life-time experiences are thought to influence the risk to develop the neurodegenerative disorder Alzheimer’s disease (AD). In particular, early-life stress (ES) may modulate the onset and progression of AD. There is recent evidence by our group and others that AD-related neuropathological progression and the associated neuroimmune responses are modulated by ES in the classic APPswe/PS1dE9 mouse model for AD. We here extend our previous study on ES mediated modulation of neuropathology and neuroinflammation and address in the same cohort of mice whether ES accelerates and/or aggravates AD-induced cognitive decline and alterations in the process of adult hippocampal neurogenesis (AHN), a form of brain plasticity. Chronic ES was induced by limiting bedding and nesting material during the first postnatal week and is known to induce cognitive deficits by 4 months in wild type (WT) mice. The onset of cognitive decline in APP/PS1 mice generally starts around 6 months of age. We here tested mice at ages 2–4 months to study acceleration and at ages 8–10 months for aggravation of the APP/PS1 phenotype. ES-exposed WT and APP/PS1 mice were able to perform the object recognition (ORT) and location tasks (OLT) at 2 months of age. Interestingly, at 3 months, ES induced impairments in the performance of the OLT in WT, but not in APP/PS1 mice. APP/PS1 mice exhibited alterations in hippocampal cell proliferation and differentiation, but ES exposure did not further change this. At 9 months, APP/PS1 mice exhibited impaired performance in the Morris Water Maze (MWM) task, as well as reductions in markers of the AHN process, which were not further modulated by ES exposure. In addition, we observed a so far unreported hyperactivity in ES-exposed mice at 8 months of age, which hampered assessment of cognitive functions in the ORT and OLT. In conclusion, while ES has been reported to modulate AD neuropathology and neuroinflammation before, it failed to accelerate or aggravate the decline in cognition or the process of AHN in APP/PS1 mice at ages 2–4 and 8–10 months. Future studies are needed to unravel how ES might affect the vulnerability to develop AD

Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer's disease mouse model

Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer's disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this. We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid β (Aβ) pathology at an early (4 month old) and at a more advanced pathological (10 month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Aβ neuropathology. ES exposure resulted in a reduction of cell-associated amyloid in 4 month old APP/PS1 mice, but in an exacerbation of Aβ plaque load at 10 months of age, demonstrating that ES affects Aβ load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Aβ neuropathology. In WT mice, immediately following ES exposure (P9), Iba1-immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1β expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4 months, while these changes resolved by 10 months of age. Finally, Aβ neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4 months, which was further enhanced by ES, whereas the microglial response to Aβ neuropathology, as measured by Iba1 and CD11b, was less prominent after ES at 10 months of age. Finally, the hippocampus appears to be more vulnerable for these ES-induced effects, since ES did not affect Aβ neuropathology and neuroinflammation in the entorhinal cortex of adult ES exposed mice. Overall, our results demonstrate that ES exposure has both immediate and lasting effects on the neuroinflammatory response. In the context of AD, such alterations in neuroinflammation might contribute to aggravated neuropathology in ES exposed mice, hence altering disease progression. This indicates that, at least in a genetic context, ES could aggravate AD pathology