Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.

Exercise Training Ameliorates Cognitive Dysfunction in Amyloid Beta-injected Rat Model: Possible Mechanisms of Angiostatin/VEGF Signaling

Vascular endothelial growth factor (VEGF) regulates angio/neurogenesis and also tightly links to the pathogenesis of Alzheimer’s disease (AD). Although exercise has a beneficial effect on neurovascular function and cognitive function, the direct effect of exercise on VEGF-related signaling and cognitive deficit in AD are incompletely understood. Therefore, the purpose of this study was to investigate the protective effect of exercise on angiostatin/VEGF cascade and cognitive function in AD model rats. Wistar male rats were randomly divided into five groups: control (CON), injection of DMSO (Sham-CON), CON-exercise (sham-EX), intrahippocampal injection of Aβ (AD), and AD-exercise (AD-EX). Rats in EX groups underwent treadmill exercise for 4 weeks, then the cognitive function was measured by the Morris Water Maze (MWM) test. mRNA levels of HIF-1, VEGF, VEGFR2, and angiostatin were determined by RT-PCR. We found that cognitive function was impaired in AD rats, but exercise training improved it. Moreover, exercise training increased the reduced mRNA expression level of VEGF signaling, including HIF1α, VEGF, and VEGFR2 in the hippocampus from AD rats. Also, the mRNA expression level of angiostatin was elevated in the hippocampus from AD rats, and exercise training abrogated its expression. Our findings suggest that exercise training improves cognitive function in AD, possibly through enhancing VEGF signaling and reducing angiostatin.

Responsive Expression of MafF to β-Amyloid-Induced Oxidative Stress

The small musculoaponeurotic fibrosarcoma (sMaf) proteins MafF, MafG, and MafK are basic region leucine zipper- (bZIP-) type transcription factors and display tissue- or stimulus-specific expression patterns. As the oxidative stress reactive proteins, sMafs are implicated in various neurological disorders. In the present study, the expressions of sMafs were investigated across five databases gathering transcriptomic data from 74 Alzheimer’s disease (AD) patients and 66 controls in the Gene Expression Omnibus (GEO) database. The expression of MafF was increased in the hippocampus of AD patients, which was negatively correlated with the expression of the glutamate cysteine ligase catalytic subunit (GCLC). Furthermore, MafF was significantly increased in patients with Braak stage V-VI, compared to those with Braak stage III-IV. β-Amyloid (Aβ), a strong inducer of oxidative stress, plays a crucial role in the pathogenesis of AD. The responsive expressions of sMafs to Aβ-induced oxidative stress were studied in the APP/PS1 mouse model of AD, Aβ intrahippocampal injection rats, and several human cell lines from different tissue origins. This study revealed that only the induction of MafF was accompanied with reduction of GCLC and glutathione (GSH). MafF knockdown suppressed the increase of GSH induced by Aβ. Among sMafs, MafF is the most responsive to Aβ-induced oxidative stress and might potentiate the inhibition of antioxidation. These results provide a better understanding of sMaf modulation in AD and highlight MafF as a potential therapeutic target in AD.

TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease

TDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.

Metabolic Syndrome Exacerbates the Recognition Memory Impairment and Oxidative-Inflammatory Response in Rats with an Intrahippocampal Injection of Amyloid Beta 1–42

An important worldwide health problem as the result of current lifestyle is metabolic syndrome (MS). It has been shown that MS induced by a high-calorie diet (HCD) in rats produces cognitive deterioration in the novel object recognition test (NORt) and decreases synaptic connections and dendritic order in the hippocampus and temporal cortex. However, it is unknown whether MS induced by an HCD participates in the cognitive process observed with the injection of Aβ1–42 into the hippocampus of rats as a model of Alzheimer disease (AD). The induction of MS in rats produces a deterioration in NORt; however, rats with MS injected with Aβ1–42 show a major deterioration in the cognitive process. This event could be explained by the increment in the oxidative stress in both cases studied (MS and Aβ1–42): together, the hippocampus and temporal cortex produce an enhancer effect. In the same way, we observed an increment in interleukin-1β, TNF-α, and GFAP, indicative of exacerbated inflammatory processes by the combination of MS and Aβ1–42. We can conclude that MS might play a key role in the apparition and development of cognitive disorders, including AD. We propose that metabolic theory is important to explain the apparition of cognitive diseases.

Lactobacilli and bifidobacteria ameliorate memory and learning deficits and oxidative stress in β-amyloid (1–42) injected rats

The gastrointestinal microbiota affects brain function, including memory and learning. In this study we investigated the effects of probiotics on memory and oxidative stress biomarkers in an experimental model of Alzheimer’s disease. Sixty rats were randomly divided into 5 groups: control; control-probiotics, which received probiotics for 8 weeks; sham operation, which received an intrahippocampal injection of phosphate-buffered saline; Alzheimer, which received an intrahippocampal injection of β-amyloid (Aβ1–42); and Alzheimer-probiotics, which in addition to being injected with Aβ1–42, received 2 g (1 × 1010 CFU/g) of probiotics (Lactobacillus acidophilus, L. fermentum, Bifidobacterium lactis, and B. longum) for 8 weeks. Memory and learning were measured using the Morris water maze, and oxidative stress biomarkers in the hippocampus were measured using ELISA kits. Morris water maze results indicated that compared with the Alzheimer group, the Alzheimer-probiotics group had significantly improved spatial memory, including shorter escape latency and travelled distance and greater time spent in the target quadrant. There was also improvement in oxidative stress biomarkers such as increased malondialdehyde levels and superoxide dismutase activity following the β-amyloid injection. Overall, it seems that probiotics play a role in improving memory deficit and inhibiting the pathological mechanisms of Alzheimer’s disease by modifying microbiota.