Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)

Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development

Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: Relevance to AD

The sporadic nature in over 90% of Alzheimer\u27s disease (AD) cases, the differential susceptibility and course of illness, and latent onset of the disease suggest involvement of an environmental component in the etiology of late onset AD (LOAD). Recent reports from our lab have demonstrated that molecular alterations favor abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with infantile lead (Pb) exposure (Bihaqi and Zawia, 2013). Here we report that developmental Pb exposure results in elevation of protein and mRNA levels of tau in aged mice. Western blot analysis revealed aberrant site-specific tau hyperphosphorylation accompanied by elevated cyclin dependent kinase 5 (CDK5) levels in aged mice with prior Pb exposure. Mice with developmental Pb exposure also displayed altered protein ratio of p35/p25 with more Serine/Threonine phosphatase activity at old age. These changes favored increase in tau phosphorylation, thus providing evidence that neurodegenerative diseases may be in part due to environmental influences that occur during development

Infantile exposure to lead and late-age cognitive decline: Relevance to AD

Background: Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer\u27s disease (AD). Methods: Morris, Y, and the elevated plus mazes were used. Western blot, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay were used to study the levels of AD biomarkers. Results: Cognitive impairment was observed in mice exposed as infants but not as adults. Overexpression of AD-related genes (amyloid beta precursor protein and β-site amyloid precursor protein cleaving enzyme 1) and their products, as well as their transcriptional regulator—specificity protein 1 (Sp1)—occurred only in older mice with developmental exposure to Pb. Conclusions: A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age

Early-life exposure to lead (Pb) alters the expression of microRNA that target proteins associated with Alzheimer’s disease

There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 hours after birth) to PND 20 via their mother’s milk, brain tissue was harvested at PND 20, 180, or 700 and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR- 29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins

Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer\u27s disease

Background: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer\u27s disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. Methods: SH-SY5Y cells exposed to thrombin concentrations (10–100 nM) +/- 250 nM dabigatran for 24 h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to determine DNA binding of NFkB. Western blotting, qRT-PCR and ELISA were used to measure the protein, mRNA, and activity levels of known AD hallmarks and signaling molecules. Results: Dabigatran treatment attenuated thrombin-induced increase in DNA binding of NFκB by 175% at 50 nM and by 77% at 100 nM thrombin concentration. Thrombin also augmented accumulation of Aβ protein expression and phosphorylation of p38 MAPK, a downstream molecule in the signaling cascade, expression of pro-apoptotic mediator caspase 3, APP, tTau and pTau. Additionally, thrombin increased BACE1 activity, GSK3β expression, and APP, BACE1, Tau and GSK3β mRNA levels. Co-incubation with dabigatran attenuated thrombin-induced increases in the protein, mRNA, and activities of the aforesaid molecules to various extents (between −31% and −283%). Conclusion: Our data demonstrates that thrombin promotes AD-related pathological changes in neuronal cultures and suggests that use of direct oral anticoagulants may provide a therapeutic benefit against thrombin-driven neuroinflammation and downstream pathology in AD

Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer’s Disease and Related Disorders

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes

LAPORAN PELAKSANAAN KKN REGULER DARING UNIVERSITAS AHMAD DAHLAN PERIODE 79 TAHUN AKADEMIK 2019/ 2020 KELOMPOK I.B.1

Kuliah Kerja Nyata (KKN) merupakan suatu kegiatan perkuliahan intrakurikuler dalam bentuk pengabdian kepada masyarakat yang dilakukan mahasiswa secara interdisipliner dan lintas sektoral. Kegiatan ini ditujukan untuk mengembangkan kepekaan rasa dan kognisi sosial mahasiswa serta membantu proses pembangunan. Dengan diadakannya KKN ini, diharapkan seorang mahasiswa semakin matang dengan disiplin keilmuannya. KKN juga berupaya mewujudkan pendidikan yang lebih efektif yaitu pendidikan yang langsung dialami oleh mahasiswa. KKN regular 79 tahun akademik 2019/2020 divisi I.B.1 berlokasi di dusun Nglampar, Desa Nglegi, Kecamatan Patuk, Gunungkidul, yang dilaksanakan kurang lebih 1 (satu) bulan dari tanggal 03 Agustus hingga 07 September 2020. Mahasiswa melaksanakan program kerja yang telah disusun berdasarkan survey sebelumnya dan pengarahan dari penelitian dosen yang mengarah ke program tematik. Kegiatan KKN ini berjalan dengan lancar dan terlaksana seluruh kegiatannya walau ada beberapa kendala umum yang dialami