The Effect of Spinal Cord Injury on Beta-Amyloid Plaque Pathology in TgCRND8 Mouse Model of Alzheimer’s Disease

Background: The accumulation and aggregation of Aβ as amyloid plaques, the hallmark pathology of the Alzheimer.s disease, has been found in other neurological disorders, such as traumatic brain injury. The axonal injury may contribute to the formation of Aβ plaques. Studies to date have focused on the brain, with no investigations of spinal cord, although brain and cord share the same cellular components. Objective: We utilized a spinal cord transection model to examine whether spinal cord injury acutely induced the onset or promote the progression of Aβ plaque 3 days after injury in TgCRND8 transgenic model of AD. Methods: Spinal cord transection was performed in TgCRND8 mice and its littermate control wild type mice at the age of 3 and 20 months. Immunohistochemical reactions/ELISA assay were used to determine the extent of axonal damage and occurrence/alteration of Aβ plaques or levels of Aβ at different ages in the spinal cord of TgCRND8 mice. Results: After injury, widespread axonal pathology indicated by intra-axonal co-accumulations of APP and its product, Aβ, was observed in perilesional region of the spinal cord in the TgCRND8 mice at the age of 3 and 20 months, as compared to age-matched non-TgCRND8 mice. However, no Aβ plaques were found in the TgCRND8 mice at the age of 3 months. The 20-month-old TgCRND8 mice with established amyloidosis in spinal cord had a reduction rather than increase in plaque burden at the lesion site compared to the tissue adjacent to the injured area and corresponding area in sham mice following spinal cord transection. The lesion site of spinal cord area was occupied by CD68 positive macrophages/ activated microglia in injured mice compared to sham animals. These results indicate that spinal cord injury does not induce the acute onset and progression of Aβ plaque deposition in the spinal cord of TgCRND8 mice. Conversely, it induces the regression of Aβ plaque deposition in TgCRND8 mice. Conclusion: The findings underscore the dependence of traumatic axonal injury in governing acute Aβ plaque formation and provide evidence that Aβ plaque pathology may not play a role in secondary injury cascades following spinal cord injury.

Honokiol Nanoscale Drug Delivery System Ameliorates the Cognitive Deficits in Tgcrnd8 Mice of Alzheimer’s Disease via Inhibiting Neuropathology and Modulating Gut Microbiota

Background Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer’s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. Methods Male TgCRND8 mice were administered with Nano-HO or HO at the same dosage (20 mg/kg) by oral gavage daily for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions with the Morris Water Maze test (MWMT). Results Nano-HO and HO could significantly improve cognitive deficits and inhibit neuroinflammation via suppressing the levels of tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. In addition, Nano-HO and HO could modulate amyloid precursor protein (APP) processing and phosphorylation via suppressing β-secretase including β-site APP cleaving enzyme-1 (BACE-1) and phosphorylated APP (Thr 668), inhibiting γ-secretase including presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as enhancing Aβ-degrading enzymes such as insulin degrading enzyme (IDE) and neprilysin (NEP). Moreover, Nano-HO remarkably inhibited tau hyperphosphorylation via decreasing the levels of p-tau (Thr 205) and p-tau (Ser 404), as well as regulating tau-related apoptosis proteins including caspase-3 and Bcl-2. Furthermore, Nano-HO and HO markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. On the other hand, Nano-HO and HO prevented the alterations on the composition of gut microbiota in TgCRND8 mice. Conclusions Nano-HO was more effective than regular HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO was also more potently modulate the gut microbiota community to protect its stability as compared with that of regular HO. Our results amply indicated that HO with nano-sized drug delivery system has good potential for further development into therapeutic agent for AD treatment.

Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive memory loss. Magnolol (MN), the main active ingredient of Magnolia officinalis, possesses anti-AD effects in several experimental models of AD. In this study, we aimed to explore whether MN could ameliorate the cognitive deficits in TgCRND8 transgenic mice and to elucidate its molecular mechanisms. Male TgCRND8 mice were orally administered with MN (20 and 40 mg/kg) daily for 4 consecutive months, followed by assessing the spatial learning and memory functions using the open-field, radial arm maze, and novel object recognition tests. The results demonstrated that MN (20 and 40 mg/kg) could markedly ameliorate the cognitive deficits in TgCRND8 mice. In addition, MN significantly increased the expression of postsynaptic density protein 93 (PSD93), PSD-95, synapsin-1, synaptotagmin-1, synaptophysin (SYN), and interleukin-10 (IL-10), while markedly reduced the protein levels of tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, Aβ40, and Aβ42, and modulated the amyloid precursor protein (APP) processing and phosphorylation. Immunofluorescence showed that MN significantly suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the hippocampus and cerebral cortex of TgCRND8 mice. Mechanistic studies revealed that MN could significantly increase the ratios of p-GSK-3β (Ser9)/GSK-3β, p-Akt (Ser473)/Akt, and p-NF-κB p65/NF-κB p65. These findings indicate that MN exerted cognitive deficits improving effects via suppressing neuroinflammation, amyloid pathology, and synaptic dysfunction through regulating the PI3K/Akt/GSK-3β and NF-κB pathways, suggesting that MN is a promising naturally occurring polyphenol worthy of further developing into a therapeutic agent for AD treatment.

Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator–activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

The degeneration of cholinergic neurons is a prominent feature of Alzheimer’s disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)–mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6

ABSTRACTExtracellular β-amyloid (Aβ) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimer’s disease and related neurodegenerative dementias could serve to accurately monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to determine how Aβ and inflammatory interleukin-6 (IL6), alone or in combination, affect in vivo tissue microstructure in the TgCRND8 mouse model of Alzheimer’s-type Aβ deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1 Tesla. Images were processed using the free water elimination method and the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern consistent with reduced white matter integrity along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean diffusivity (MD), and free water (FW), and increased ‘neurite’ density (NDI) and orientation dispersion (ODI). IL6 produced a ‘protective-like’ effect on FA in TgCRND8 mice, although there were minimal microstructure changes in these mice compared IL6 expressing nTg mice. In addition, we found that NDI and ODI had an inverse relationship with the functional connectome clustering coefficient, which was affected by Aβ and IL6. The relationship between NODDI and graph theory metrics suggests that increasing the density and orientation dispersion of neurites may relate to diminished functional network organization in the brain.