Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model

International audienceDeficits in synaptic structure and function are likely to underlie cognitive impairments in Alzheimer's disease. While synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic functions. In some amyloid mouse models of Alzheimer's disease , however, synaptic deficits are preceded by hyperexcitability of glutamate synapses. In the amyloid transgenic mouse model TgCRND8, we therefore investigated whether early enhancement of gluta-matergic transmission was responsible for development of later synaptic deficits. Hippocampi from 1-month-old TgCRND8 mice revealed increased basal transmission and plasticity of glutamate synapses that was related to increased levels of tumor necrosis factor a (TNFa). Treating these 1-month-old mice for 4 weeks with the TNFa inhibitor XPro1595 prevented synaptic deficits otherwise apparent at the age of 6 months. In this mouse model at least, reversing the hyperexcitability of glutamate synapses via TNFa blockade before the onset of amyloid plaque formation prevented later synaptic deficits

Preventing synaptic deficits in Alzheimer’s disease by inhibiting tumor necrosis factor alpha signaling

The characterization of preclinical stages of Alzheimer’s disease (AD) would provide a therapeutic window for prevention. One of the challenges of developing preventive therapy for AD is to identify early biomarkers for intervention studies. We have recently shown that in the TgCRND8 transgenic AD mouse model, increased hippocampal levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and enhanced excitatory synaptic transmission were early-onset changes that occurred weeks before amyloid plaque formation. Inhibiting TNFα before plaque formation not only normalized excitatory synaptic function, but also prevented the impairment of synaptic function 4 months later. In this review paper, we will examine the potential contributions of TNFα to the alteration of brain function in preclinical AD. The prospective use of TNFα inhibitors for preventing AD will be discussed. Keywords: Amyloid precursor protein, Hippocampus, Neuroinflammation, Prevention, TgCRND8 mice, Tumor necrosis factor alpha, XPro159

Amyloidosis in Retinal Neurodegenerative Diseases

International audienceAs a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer's disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations , similar to those seen in the brain of Alzheimer's patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer's patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a " window " to the brain

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD

Alterations in hippocampal network oscillations and theta-gamma coupling arise before Aβ overproduction in a mouse model of Alzheimer's disease

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Expression of Phenotypic Astrocyte Marker Is Increased in a Transgenic Mouse Model of Alzheimer's Disease versus Age-Matched Controls: A Presymptomatic Stage Study.

Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aβ production from the Aβ precursor protein (APP), we assessed a putative correlation between APP/Aβ and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice. While Western blots revealed significant APP expression, Aβ was not detectable by Western blot or ELISA attesting that 3-month-old, APPswe/PS1dE9 mice are at a presymptomatic stage of AD-like pathology. Western blots were also used to show increased GFAP expression in transgenic mice that positively correlated with both TNFα and APP, which were also mutually correlated. Subregional immunohistochemical quantification of phenotypic (GFAP) and functional (TSPO) markers of astrocyte activation indicated a selective and significant increase in GFAP-immunoreactive (IR) cells in the dentate gyrus of APPswe/PS1dE9 mice. Our data suggest that subtle morphological and phenotypic alterations, compatible with the engagement of astrocyte along the activation pathway, occur in the hippocampus already at the presymptomatic stage of AD

TgCRND8 mice show sleep-wake cycle disruption at early and advanced pathological stages.

<p>Hourly time courses (<b>A</b>) and cumulative percent duration (<b>B</b> and <b>C</b>) of wake, NREM and REM sleep across the light and dark phases at 3 (NTg n = 7, Tg n = 8), 7 (NTg n = 5, Tg n = 7) and 11(NTg n = 6, Tg n = 4) months of age. (<b>B)</b> During the dark phase, 3, 7 and 11-month-old TgCRND8 spend more time awake and less time in NREM sleep in comparison to NTg. Three and 7-month-old TgCRND8 mice also show a significant decrease in the percent time spent in REM sleep during the dark phase in comparison to NTg. (<b>C)</b> During the light phase, 3, 7 and 11-month-old TgCRND8 spend more time awake and less time in NREM sleep in comparison to NTg. Total time spent in REM sleep did not differ significantly between TgCRND8 and NTg during the light phase, at all ages studied. Error bars represent SEM. Panel <b>A</b> was analyzed by two-way ANOVA, followed by Bonferroni test for multiple comparisons. Panels <b>B</b> and <b>C</b> were analyzed by two-way ANOVA, followed by Tukey’s post-hoc test, * <i>P</i><0.05, ** <i>P</i><0.01, ***<i>P</i><0.001.</p

Prazosin differentially affects NREM sleep in 3.5-month-old TgCRND8 and NTg mice.

<p>Time spent in NREM sleep during the 2-hour period following administration of the α_<b>1</b>-adrenergic antagonist, prazosin, at 1 (<b>A</b>), 2 (<b>B</b>) and 5 (<b>C</b>) mg/kg versus vehicle in 3.5-month-old NTg and TgCRND8 mice. Prazosin or vehicle was administered at 10:00 AM via an intraperitoneal injection. (<b>A)</b> Treatment with Prazosin at 1 mg/kg does not significantly affect the percent time spent in NREM sleep when compared to vehicle in both NTg and TgCRND8. (<b>B)</b> At 2 mg/kg, treatment with Prazosin significantly increases the time spent in NREM sleep in comparison to vehicle in NTg mice only. The observed increase in NREM sleep in NTg following treatment with 2 mg/kg prazosin differed significantly from time spent in NREM sleep following treatment with 2 mg/kg in TgCRND8. (<b>C)</b> At 5 mg/kg, prazosin significantly increases time spent in NREM sleep in both NTg and TgCRND8 mice. Error bars represent SEM. NTg vehicle n = 11, NTg 1, 2 and 5 mg/kg n = 8, Tg vehicle n = 11, Tg 1 and 2 mg/kg n = 9, Tg 5 mg/kg n = 6. Fig <b>5A</b>, <b>5B</b> and <b>5C</b> were analyzed by individual two-way ANOVAs comparing each prazosin dose to vehicle, followed by Tukey’s post-hoc or simple effects analysis where appropriate, * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001.</p

Quantification of Aβ₄₂ levels from key regions regulating the sleep-wake cycle.

<p>Quantification of total Aβ_<b>42</b> levels from the prefrontal cortex, hypothalamus, thalamus and brainstem of 3 (n = 7), 7 (n = 9) and 11-month-old (n = 7) TgCRND8 mice. Picograms (pg) of total Aβ_<b>42</b> are normalized to milligrams (mg) of protein per sample. (<b>A, B and C)</b> At 3, 7 and 11 months of age the prefrontal cortex contains the highest level of total Aβ_<b>42</b>, differing significantly from the hypothalamus, thalamus and brainstem. (<b>C)</b> At 11 months of age, the thalamus contains significantly higher total Aβ_<b>42</b> than the brainstem. (<b>D)</b> Progression of total Aβ_<b>42</b> overexpression in the prefrontal cortex, hypothalamus, thalamus and brainstem at 3, 7 and 11 months of age. Error bars represent SEM. Fig <b>4A</b>, <b>4B</b> and <b>4C</b> were analyzed by one-way ANOVA for the effect of brain region at a given age, followed by Tukey’s post-hoc. * Denotes a significant difference between the prefrontal cortex and each other region. # Denotes a significant difference between the thalamus and the brainstem. */^#<i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001.</p