Alzheimer's Disease-like Pathology Research Articles

Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model.

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.

Changes in Glial Support of the Hippocampus during the Development of an Alzheimer's Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1.

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer’s disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment.

Exosomes obtained from amyloid-beta toxicity applied cells induce Alzheimer's disease-like pathology in the brain of C57BL/6 mice

Exosomes obtained from amyloid-beta toxicity applied cells induce Alzheimer's disease-like pathology in the brain of C57BL/6 mice

A Non-Human Primate Model with Alzheimer's Disease-Like Pathology Induced by Hippocampal Overexpression of Human Tau

A Non-Human Primate Model with Alzheimer's Disease-Like Pathology Induced by Hippocampal Overexpression of Human Tau

Effects of repetitive mild traumatic brain injury on neural immune signaling and Alzheimer's disease-like pathology.

Repeated mild traumatic brain injuries (mTBIs) sustained within a "window of vulnerability" can lead to a cumulative severity of outcomes such as memory impairment, depression, and long-term development of amyloid beta (Aβ) pathology and neurofibrillary tangles. We previously reported that acute increases in neural immune signaling within the MAPK pathway and expression of pro-inflammatory cytokines were associated with worse long-term cognitive outcome in a weight-drop mouse model of repetitive mTBI. We hypothesized that an increasing number of injuries would lead to changes in the kinetics of neural immune signaling and that expression of cytokines would correlate with increased Aβ and tau pathology in the 3xTg mouse model. 3xTg mice at 3-4mo of age were subjected to 1x, 3x, or 5x weight-drop closed head injuries (CHI) spaced once-daily. Animals were sacrificed and brains harvested at 30min, 4h, 24h, or 1-month after the final CHI (n=4-6/time point/injury group). 32 cytokines and 10 MAPK phospho-proteins were measured by Luminex in cortical tissues. Immunohistochemistry was conducted for phospho-tau (S262/T263) and Aβ (6E10 antibody). We observed distinct temporal dynamics in MAPK pathway signaling and cytokine expression between 1x, 3x, and 5xCHI mice. 1xCHI mice showed maximal MAPK pathway activation at 30min (e.g, phospho-p38, pStat1) which then decreased concomitantly with increased expression of pro-inflammatory cytokines (e.g., RANTES, IL-17) at 24h. In contrast, 3xCHI yielded MAPK activation similar to 1xCHI at 30min, but continued to increase until 24h. 5xCHI showed an accelerated signaling response peak at 4h. Further, multiple cytokines were increased at 24h after 3x and/or 5xCHI compared to 1xCHI (e.g., VEGF, IL-9, IL-17; p<0.05). In terms of pathology, Aβ was increased at 4,24h (p<0.05) and phospho-tau was increased after 1mo in 5xCHI animals compared to sham controls (p<0.01). Moreover, positive trends were observed between phospho-tau at 1mo and expression of pro-inflammatory cytokines IL-15 and M-CSF (p=0.13, FDR-corrected). Repetitive mTBI yielded amplified and sustained MAPK pathway signaling at short time points and a relationship between cytokine expression and tau phosphorylation after 1mo. These findings suggest that modulation of the MAPK pathway may be a promising therapeutic target for rmTBI.

Altered locus coeruleus activity and neurochemistry in the presence of Alzheimer's disease-like hyperphosphorylated tau pathology.

The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, develops tau pathology prior to other brain regions and later degenerates in Alzheimer's disease (AD). Emergence of prodromal symptoms before cognitive impairment is evident, such as anxiety, agitation, and sleep disturbances, parallels development of hyperphosphorylated tau in the LC. Although pathogenic tau can alter the activity of other neurons, and noradrenergic dysfunction likely contributes to prodromal AD symptoms, the consequences of hyperphosphorylated tau on LC function are unknown. TgF344-AD rats, which develop hyperphosphorylated tau in the LC prior to other brain regions, and wild-type (WT) littermates aged 6 and 15 months (3-10 rats/group) were used. Baseline and footshock (0.5ms and 5ms 10mA)-evoked single unit LC activity (27-111 neurons/group) were recorded in chloral hydrate anesthetized rats. LC sections from duplicate groups of rats were immunostained for tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) to proxy NE synthesis capacity, NE transporter (NET) to assess somatodendritic LC integrity and NE uptake, monoamine oxidase A (MAOA) to evaluate NE metabolism, galanin to measure peptide co-transmitter levels, and GAD67 to investigate local inhibitory networks (3-4 slices/animal, 2-7 animals/group). Grayscaled fluorescence was measured in ImageJ. Electrophysiology revealed a trend towards increased LC baseline firing rates in WT and TgF344-AD rats at 15 months vs 6 months, with no genotype differences. Footshock-evoked LC activity tended to be exaggerated in TgF344-AD rats at 6 months, but blunted or unchanged at 15 months compared to WT. Immunofluorescence indicated decreased NET in TgF344-AD rats at 6 months, with both genotypes showing a reduction at 15 months compared to younger animals. GAD67 was significantly higher in 15-month animals compared to 6 months, with no genotype differences. No significant effects of genotype or age were found for MAOA, DBH, or galanin. These results suggest early LC dysfunction that coincides with the onset of hyperphosphorylated tau pathology. Further studies investigating the time course of LC dysfunction in AD, as well as therapies aimed at correcting these abnormalities, are warranted.

OGDHL ameliorates cognitive impairment and Alzheimer's disease-like pathology via activating Wnt/β-catenin signaling in Alzheimer's disease mice

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases related to several types of pathophysiological signs, including β-amyloid (Aβ) plaque accumulation, neuroinflammation, and neurofibrillary tangles. Similar to one of the three subunits of α-ketoglutarate dehydrogenase complex (KGDHC), oxoglutarate dehydrogenase-like (OGDHL) appears to be downregulated in triple-transgenic Alzheimer's (3 × Tg-AD) mice. KGDHC activity is specifically reduced in the brains of people with AD. However, the underlying mechanism of OGDHL in the cause of AD is still unknown. Herein, we confirmed the low expression of OGDHL in the brain of 3 × Tg-AD based on real-time quantitative PCR, Western blot, and immunohistochemistry. We also found that the upregulation of OGDHL can reduce the memory deficits of 3 × Tg-AD mice, thereby reminding its nervous system neuroprotective effect in AD. Next, we confirmed that the increase in OGDHL could reduce neuroinflammation, amyloid plaque load, and tau phosphorylation in 3 × Tg-AD mice. Additionally, we showed that the overexpression of OGDHL could activate Wnt/β-catenin signaling based on the expression of Wnt7B in vitro. Taken together, the results show that the rise of OGDHL reasonably improves the cognitive functions according to the activation of the Wnt/β-catenin signaling pathway. Therefore, this enzyme may be a potential strategy for AD treatment.

MiR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling

IntroductionMir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1–42. MethodsTo create a model of AD, SH-SY5Y cells were treated with Aβ1–42 and mice received intracerebroventricular injections of Aβ1–42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations. ResultsAβ1–42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1–42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway. ConclusionsOur research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.

Dual prophylactic/therapeutic potential of date seed, and nigella and olive oils-based nutraceutical formulation in rats with experimentally-induced Alzheimer's disease: A mechanistic insight

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a multifactorial etiology and significantly increasing incidence during the last decade. Hence, developing an effective therapy is crucial for public health. The current study aimed to examine the dual prophylactic/therapeutic potential of a nutraceutical formula based on aqueous extract of roasted date seeds, and nigella and virgin-olive oils against experimentally-induced Alzheimer's disease in rats. Alzheimer's disease-like pathology was induced in male Wistar rats using oral CuSO4 (200 mg/Kg/day for two months). The nutraceutical formula was given orally to experimental animals (10 mL/kg/d) for 14 days before (as prophylaxis) and after Alzheimer's disease induction and its therapeutic effect in both cases is tested in comparison to donepezil (0.5 mg/kg/d). The nutraceutical formula was found to ameliorate the CuSO4-induced neuronal damage and regenerate the affected hippocampus tissue and significantly improvemed in learning ability. The formula was also effective in decreasing brain amyloid-β, tau protein, TNF-α level, iNOS level in hippocampus, oxidative stress level, and inhibiting acetylcholinesterase activity and expression in brain and hippocampus, respectively. Further, an increase in GSH levels, activities of SOD, and GST and levels of hippocampus ADAM 17 and brain phospholipids was observed. In conclusion, the studied nutraceutical formula is proved to be effective in ameliorating Alzheimer’s neurodegenerative progression with added-prophylactic potential.

Erratum: Forny-Germano et al., "Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates".

Erratum: Forny-Germano et al., "Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates".

Embryonic proteoglycans regulate monoamines in the rat frontal cortex and hippocampus in Alzheimer's disease-like pathology

Using the rat Alzheimer's disease (AD)-like model we have analyzed the hippocampal short-term potentiation, levels of monoamines, and morphological changes in the hippocampal and cortical neurons after the administration of proteoglycans of embryonic origin (PEG). Results showed that the levels of monoamines and especially norepinephrine in the target AD brain structures were found elevated, except serotonin, which was unaffected in the hippocampus, but decreased in the frontal cortex. These changes were accompanied by the substantial structural damage of cortical and hippocampal neurons. PEG was able to reverse most of these changes. In addition, PEG administration had regime-dependent effects on a short-term potentiation pattern of hippocampal neurons. The elevated levels of key elements of brain monoaminergic system in the model of AD support the hypothesis of the important role of monoamines in the excessive synaptic excitation resulting in cognitive dysfunction in AD brain. The neuroprotective effect of PEG, as manifested by the recovery of the monoaminergic system, suggests this bioactive substance as a perspective therapeutic agent for the treatment of AD.

Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

Introduction Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2. Methods The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, Aβ, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR. Results The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. Aβ and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Conclusion Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.

Protective role of functional food in cognitive deficit in young and senile rats.

Cognitive decline and neurodegenerative diseases pose a significant burden on healthcare resources both in developed and developing countries which is a major socio-economic and healthcare concern. Alzheimer's disease is the most common form of progressive neurodegenerative dementia of the aged brain. Aluminum is a constituent of antacids, deodorants, kitchenware and food additives which allows easy access into the body posing risk to development of senile dementia of Alzheimer's type. Virgin coconut oil was declared as a potential cognitive strengthener. Assessment of cognitive and memory-enhancing effects of virgin coconut oil in senile and young rats to gain vital insights into its effective use in the prevention of neurodegeneration in dementia/Alzheimer's disease-like manifestations and alleviate cognitive dysfunction and learning impairment with neuronal damage imparted by daily oral intake of aluminum. Alzheimer's disease-like symptoms and memory impairment were experimentally induced using oral anhydrous aluminum chloride given daily for five successive weeks in young and old age albino rats. Treatment groups received virgin coconut oil to assess protection during the experimental period. Behavioral test, Morris water maze was conducted before/after induction/treatment. At the end of the experimental period, cholinergic, dopaminergic, noradrenergic and serotonergic neurotransmission as well as brain-derived neurotrophic factor were being investigated, in addition to immunochemical and histopathological examination of targeted brain regions. Virgin coconut oil significantly improved cholinergic activity and monoaminergic neurotransmission. Moreover, immunochemical and histopathological examination revealed marked protection with virgin coconut oil against aluminum-induced Alzheimer's disease-like pathology and cognitive deficit.

Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-γ

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.

Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: An in vitro approach

Environmental pollutant, Lead (Pb) is known to induce neurotoxicity in human. The central nervous system is the most vulnerable to the minute levels of Pb induced toxicity. Pb has been linked to Alzheimer's disease (AD) as a probable risk factor, as it shows epigenetic and developmental link associated with Alzheimer's disease-like pathology. Beta amyloid peptides were considered as the crucial factors in the beta amyloid plaque formation in Alzheimer's disease brain. In this context, we investigated the molecular mechanism involved in the development of Pb induced Alzheimer's disease in in vitro. Previous data from our studies have reported that Pb in the presence of beta Amyloid peptide (1–40) and (25–35) induces more apoptosis than individual exposures. Here, to further evaluate the molecular mechanism underlying Pb induced Alzheimer's disease; we focussed on the involvement of calcium signalling in inducing cell death. Our experimental observations suggesting that Pb in the presence of beta amyloid peptide alters intracellular calcium levels, which leads to the increased beta-secretase activity, which further promotes the generation of beta amyloid peptides. It also showed depression in the levels of GAP-43 expression, inhibition of PKC activity and altering synaptic activity further leads to cell death.

Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer's Disease-Like Pathology in Rats.

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

Extracellular Vesicles: A Possible Link between HIV and Alzheimer's Disease-Like Pathology in HIV Subjects?

The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer’s disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.

The fruit of Crataegus pinnatifida ameliorates memory deficits in β-amyloid protein-induced Alzheimer's disease mouse model

Ethnopharmacological relevanceThe fruit of Crataegus pinnatifida is a traditional medicine widely used as digestive drug in East Asia. Although Chinese herbal medicine used it for mental health, scientific evidence does not exist, yet. Aims of studyThe aim of this study is to show that the ethanol extract of the fruit of Crataegus pinnatifida (CPE) has neuroprotective effect on Alzheimer’ disease model mice. Materials and methodsIntracerebroventricular injection of Aβ was used to induce Alzheimer's disease-like pathology. Passive avoidance and Y-maze tasks were used to examine the effect of CPE on memory impairments by Aβ. Immunohistochemistry was used to examine the effect of CPE on glial activation. ThT assay was used to observe the effect of CPE on Aβ aggregation. MTT and LDH release assays were utilized to examine effects of CPE on Aβ-induced cytotoxicity. ResultsCPE prevented memory deficit in Aβ-induced memory impairment model. Moreover, CPE prevented glial activation in the hippocampus of Aβ-injected model. In in vitro test, CPE inhibited Aβ fibril formation in a concentration-dependent manner. CPE also caused disaggregation of Aβ fibrils. Along with this, CPE blocked neuronal cell death induced by Aβ. ConclusionsCollectively, these experimental findings demonstrated that CPE could be a candidate for development of AD therapy.

Choline Supplementation Ameliorates Behavioral Deficits and Alzheimer's Disease-Like Pathology in Transgenic APP/PS1 Mice.

Alzheimer's disease (AD) is a detrimental neurodegenerative disease and has no known effective treatment. The essential nutrient choline potentially plays an important role in cognition. Perinatal choline supplementation (CS) is critical for memory performance. Findings have shown that postnatal choline-containing compounds enhance memory functions in populations with memory impairments. However, whether CS can be targeted to decelerate the progression of AD remains unknown. APP/PS1 mice and their wild-type littermates are fed either a control or CS diet from 2 to 11 months of age. As compared to WT mice, APP/PS1 mice on the control diet are characterized by the reduction in the number of cholinergic neurons in the basal forebrain, reduced cholinergic fiber staining intensity in the amygdala, and reduced hippocampal and cerebral cortical levels of choline and acetylcholine. CS partially prevents these changes and ameliorates cognitive deficits and anxiety. Furthermore, amyloid-β deposition and microgliosis are decreased in the APP/PS1 mice fed a CS diet. These effects may have been due to inhibition of NLRP3 inflammasome activation and restoration of synapse membrane formation. These findings reveal a beneficial effect of CS on AD progression during adulthood and provide a likely therapeutic intervention for AD patients.

Glucocerebrosidase regulators SCARB2 and TFEB are up-regulated in Lewy body disease brain

Mutations in the glucocerebrosidase (GCase) gene (GBA) and GCase deficiency are major risk factors for Lewy body diseases. Decreased GCase activity enhances alpha-synuclein aggregation and disease development. Lysosomal integral membrane protein type 2, encoded by SCARB2, binds GCase targeting it to lysosomes and transcription factor EB (Tfeb) regulates lysosomal proteostasis. Our aim was to find out if GCase deficiency in Lewy body diseases is accompanied by SCARB2 and TFEB deregulation at the transcriptional level involving alternative splicing as well. Relative mRNA expression of two SCARB2 and two TFEB transcripts was studied by real-time PCR in post-mortem brain samples of cases with pure Lewy body pathology (LBP), cases with concomitant LBP and Alzheimer disease-like pathology, and controls. TFEB expression was increased in the temporal cortex and caudate nucleus of LBP cases, and SCARB2 was differentially expressed. Female-gender associated overexpression of all transcripts was found in the caudate nucleus, and disease duration associated TFEB expression changes in the temporal cortex. SCARB2 and TFEB expression correlated negatively with GBA mRNA expression in the temporal cortex. Our findings show disease-specific deregulation of TFEB and SCARB2 expression affecting alternative promoter usage and alternative splicing in Lewy body diseases.