Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

Homocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD

Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

Homocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD

Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities

Alzheimer\u27s disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked posttraumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies

Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice

Alzheimer's disease (AD) is an age-associated progressive neurodegenerative disorder with dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that homocysteic acid (HA) may be one of the pathological biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal amyloid-beta (Aβ) peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathological 3xTg-AD mice exhibited higher levels of HA in the hippocampus than did age-matched nontransgenic mice, suggesting that HA accumulation may precede both Aβ and tau pathologies. We then fed 3-month-old 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to increase the HA levels in the brain. Concomitantly, mice received either saline or anti-HA antibody intraventricularly via a guide cannula every 3 days during the course of the B6-deficient diet. We found that mice that received anti-HA antibody significantly resisted cognitive impairment induced by vitamin B6 deficiency and that AD-related pathological changes in their brains was attenuated compared with the saline-injected control group. A similar neuroprotective effect was observed in 12-month-old 3xTg-AD mice that received anti-HA antibody injections while receiving the regular diet. We conclude that increased brain HA triggers memory impairment and that this condition deteriorates with amyloid and leads to subsequent neurodegeneration in mouse models of AD

Impaired Spatial Reorientation in the 3xTg-AD Mouse Model of Alzheimer's Disease.

In early Alzheimer's disease (AD) spatial navigation is impaired; however, the precise cause of this impairment is unclear. Recent evidence suggests that getting lost is one of the first impairments to emerge in AD. It is possible that getting lost represents a failure to use distal cues to get oriented in space. Therefore, we set out to look for impaired use of distal cues for spatial orientation in a mouse model of amyloidosis (3xTg-AD). To do this, we trained mice to shuttle to the end of a track and back to an enclosed start box to receive a water reward. Then, mice were trained to stop in an unmarked reward zone to receive a brain stimulation reward. The time required to remain in the zone for a reward was increased across training, and the track was positioned in a random start location for each trial. We found that 6-month female, but not 3-month female, 6-month male, or 12-month male, 3xTg-AD mice were impaired. 6-month male and female mice had only intracellular pathology and male mice had less pathology, particularly in the dorsal hippocampus. Thus, AD may cause spatial disorientation as a result of impaired use of landmarks

Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations

SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production

In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic Ca2+ is maintained at low levels by pumping Ca2+ into stores in the endoplasmic reticulum (ER) via the sarco ER Ca2+-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic Ca2+, whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating Ca2+ clearance and exaggerating inositol 1,4,5-trisphosphate–mediated Ca2+ liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid β production. Our results point to a physiological role for the presenilins in Ca2+ signaling via regulation of the SERCA pump

Spatial Frequency Domain Imaging of Intrinsic Optical Property Contrast in a Mouse Model of Alzheimer’s Disease

Extensive changes in neural tissue structure and function accompanying Alzheimer’s disease (AD) suggest that intrinsic signal optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work, we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-contact, quantitative in vivo optical imaging of brain tissue composition and function in a triple transgenic mouse AD model (3xTg). SFDI was used to generate optical absorption and scattering maps at up to 17 wavelengths from 650 to 970 nm in 20-month-old 3xTg mice (n = 4) and age-matched controls (n = 6). Wavelength-dependent optical properties were used to form images of tissue hemoglobin (oxy-, deoxy-, and total), oxygen saturation, and water. Significant baseline contrast was observed with 13–26% higher average scattering values and elevated water content (52 ± 2% vs. 31 ± 1%); reduced total tissue hemoglobin content (127 ± 9 μM vs. 174 ± 6 μM); and lower tissue oxygen saturation (57 ± 2% vs. 69 ± 3%) in AD vs. control mice. Oxygen inhalation challenges (100% oxygen) resulted in increased levels of tissue oxy-hemoglobin (ctO2Hb) and commensurate reductions in deoxy-hemoglobin (ctHHb), with ~60–70% slower response times and ~7 μM vs. ~14 μM overall changes for 3xTg vs. controls, respectively. Our results show that SFDI is capable of revealing quantitative functional contrast in an AD model and may be a useful method for studying dynamic alterations in AD neural tissue composition and physiology

Impact of white adipose tissue in AD pathology

Introduction: Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences has suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. In addition, novel studies has suggested that AD induces peripheral metabolic alterations, facilitating the development of diabetes. Overall, these studies suggest that there is an important two-way crosstalk between AD and peripheral metabolic disorders. Here, we seek to understand the mechanisms underlying this association and we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and alterations in this organ may affect both types of disorders. Methods: Here, we used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from wt and 3xTg-AD mice. Moreover, similar techniques were used in the brain of 3xTg-AD mice that received white fat pads from wt and 3xTg-AD donors to determine any changes in amyloid and tau pathology. Results: Our study shows that 3xTg-AD mice develop significant peripheral metabolic alterations which in turn affected the white adipose tissue biology. Moreover, adipose tissue transplanted from donor 3xTg-AD and wt mice into recipient 3xTg-AD mice indicate that AD associated white fat tissue induced profound AD pathology changes in recipient 3xTg-AD mice. Conclusions: Overall, our study demonstrate a novel important crosstalk between AD and peripheral metabolic disorders thought white adipose cells. A more profound understanding in these processes may turn in novel and promising therapeutic strategies for AD and metabolic illnesses.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech