Search

IntroductionClinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population.MethodsThe ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese.ResultsACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception.DiscussionACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness.HighlightsThe Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Background: Local protein synthesis and mRNA metabolism mediated by mRNP granules in the dendrites and the postsynaptic compartment is essential for synaptic remodeling and plasticity in neuronal cells. Dysregulation of these processes caused by TDP-43 proteinopathy leads to neurodegenerative diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Methods: Using biochemical analysis and imaging techniques, including super-resolution microscopy, we provide evidence, for the first time, for the postsynaptic localization of TDP-43 in mammalian synapses and we show that TDP-43 is a component of neuronal mRNP granules. Results: With activity stimulation and various molecular approaches, we further demonstrate activity-dependent mRNP granule dynamics involving disassembly of mRNP granules, release of mRNAs, activation of local protein translation, and the impairment of granule disassembly in cellular, animal and human models of TDP-43 proteinopathy. Conclusion: Our study elucidates the interplay between TDP-43 and neuronal mRNP granules in normal physiology and TDP-43 proteinopathy in the regulation of local protein translation and mRNA metabolism in the postsynaptic compartment.

TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

A feasible design is made to measure three protein/protein interactions to visualize signal pathways by time-lapse Förster resonance energy transfer (FRET) microscopy. When interacting proteins are in close proximity, excitation energy is provided to allow the energy flow from the first molecule to excite the second, followed by energy transfer to the third. By phorbol ester/calcium ionophore stimulation, for example, a real-time complex formation of ectopic IκBα/ERK/WWOX occurs as measured by FRET microscopy, indicative of an ongoing functional signaling. Hyaluronan induces membrane Hyal-2 signaling, which allows FRET measurement of the complex formation of ectopic Smad4/WWOX/Hyal-2 for causing bubbling cell death. If ectopic p53 is recruited to replace Hyal-2, the resulting ectopic Smad4/WWOX/p53 complex induces membrane blebbing without cell death. Together, in this perspective review article, we demonstrate the utilization of time-lapse FRET microscopy to visualize the signaling event via the tri-molecular protein complex formation and their biological outcomes. We show an initial two-protein binding to form the driving force to jumpstart the tri-molecular execution for the signal pathway.

Background: Asian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer's disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer's Disease (ACAD), the first large dementia genetics cohort currently focuses on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: The ACAD pilot study has 7 recruiting sites (5 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and a centralized data management system in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure the protocol consistency, ACAD implemented a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. Result: As of December 2022, ACAD's pilot study has consented 606 participants, 527 participants have complete DCP data submitted to REDCap (448 Chinese, 54 Korean, and 25 Vietnamese), and more than 1,500 people have expressed interests in ACAD. The majority 66.2%)women. The age range of the sample is 60‐93 years. 47.3% have college or graduate level education. 451 participants provided a saliva (274) or a blood (177) sample. Feedback in pilot indicates a need to adapt the Early Life Enrichment inventory further to apply to wartime deprivation conditions for this population, as well as more cultural tailored neuropsychological tests. Conclusion: ACAD has learned valuable experience in interactions with ASACs and shown the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on minority, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. [ABSTRACT FROM AUTHOR]

Background: As the first large Alzheimer's Disease (AD) genetics cohort for Asians in the United States and Canada, the Asian Cohort for Alzheimer's Disease (ACAD) has adapted existing instruments to collect data on sex, genetics, medical history, and lifestyle risk factors. We hypothesize that any and all of these factors impact AD risk differently for Asians. Initially ACAD focuses on US and Canadian participants of Chinese, Korean, and Vietnamese ancestry. Method: ACAD's Clinical Workgroup reviewed commonly used dementia research questionnaires, including the NACC Uniform Data Set, Religious Order Study, and NIA‐Late‐Onset AD to select, and in some cases adapt, questions that are most appropriate for ACAD. A combination of AD clinical researchers and community outreach specialists reviewed the data collection packet, administration procedures, and consensus diagnosis process for cultural sensitivity without sacrificing scientific rigor to gather non‐genetic and lifestyle risk factor data. Result: We designed the ACAD Data Collection Packet (DCP) to create a friendly dialogue with participants through a socio‐culturally and linguistically sensitive 3‐part process. The DCP consists of some instruments already validated in Chinese, Vietnamese and Korean languages to screen for cognitive impairment (Cognitive Abilities Screening Instrument (CASI) and Modified Mini‐Mental State (3MS)). Part A collects origins, Mediterranean diet compliance, and Clinical Dementia Rating scores. The self‐administered Part B uses an adaptation of the Rush Cognitive Activity Questionnaire on early‐life enrichment. Part C structures the collection of medical history and cognitive testing with CASI vs 3MS, the Common Objects Memory Test, Category (not Letter) Fluency, and the 15‐item Clock Drawing Task. This assessment is designed to be administered either remotely or face to face. Conclusion: Over the next year, we will pilot the ACAD Data Collection Packet, to set a community standard for dementia screening among Asian Americans and Canadians that can support data harmonization across epidemiological studies. While ACAD translation accommodates Chinese, Korean, and Vietnamese at this stage, we look forward to implementing additional major Asian languages. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Variant Portal (ADVP, https://advp.niagads.org) is a curated and harmonized interactive platform providing the research community with a unified way to access and visualize the largest up‐to‐date collection of Alzheimer's disease (AD) genetic findings from >200 genome‐wide association studies (GWASs). In this study, we aim to characterize the regulatory roles and mechanisms underlying these genetic signals in AD. Methods: We analyzed all Caucasian genome‐wide significant signals in ADVP (348 genetic variants and 186 loci) using FILER (Kuksa et al., 2021) and SparkINFERNO (Kuksa et al., 2020). The SparkINFERNO high throughput system analyses framework is coupled with the FILER (https://lisanwanglab.org/FILER), a rich resource of >50,000 harmonized functional genomic datasets across many different sources including ENCODE, FANTOM5, GTEx, Roadmap, DASHR2 and others. With this systematic, hypothesis‐free analysis approach, we analyzed and ranked relevant tissue categories by quantifying the significance and enrichment of tissue‐specific enhancer overlaps with ADVP variants compared to the empirical overlap distribution for matching background (non‐AD) variants. Further integration with the AMP‐AD expression quantitative trait loci (eQTL) datasets from three brain regions (dorsolateral prefrontal cortex, cerebellum and temporal cortex), enable us to discover the potentially causal genes affected by these variants. Results: The ADVP variants were enriched in regulatory elements profiled by FANTOM5 and Roadmap Epigenomics (ChromHMM). Top tissues enriched in Roadmap enhancers include blood (OR=3.7), digestive (OR=3.5), brain (OR=2.8), and skeletal muscles (OR=2.6). 31% of the analyzed ADVP variants were identified as significant eQTLs in at least one of the three AMP‐AD eQTL datasets (FDR<0.01), and 32% among these were eQTLs in all three brain regions. Altogether, these variants targeted 130 genes (including HLA regions), of which 31 were also the nearest genes reported in ADVP. These target genes (e.g. ACE, PVR, KANSL1, NARS2) were enriched in cell junction organization, DNA repair (nucleotide‐excision repair) and acetyltransferase activity (cholinergic system), which recapitulated some of the molecular and cellular mechanisms underlying the pathogenesis of AD. Conclusions: Conducted analysis of genetic associations across >200 GWASs in ADVP and identified known AD culprit genes, relevant tissue/cell type categories, and regulatory mechanisms. [ABSTRACT FROM AUTHOR]

To better capture the polygenic architecture of Alzheimer's disease (AD), we developed a joint genetic score, MetaGRS. We incorporated genetic variants for AD and 24 other traits from two independent cohorts, NACC ( n = 3,174, training set) and UPitt ( n = 2,053, validation set). One standard deviation increase in the MetaGRS is associated with about 57% increase in the AD risk [hazard ratio (HR) = 1.577, p = 7.17 E-56], showing little difference from the HR for AD GRS alone (HR = 1.579, p = 1.20E-56), suggesting similar utility of both models. We also conducted APOE-stratified analyses to assess the role of the e4 allele on risk prediction. Similar to that of the combined model, our stratified results did not show a considerable improvement of the MetaGRS. Our study showed that the prediction power of the MetaGRS significantly outperformed that of the reference model without any genetic information, but was effectively equivalent to the prediction power of the AD GRS., Competing Interests: C-LL would like to note that the analysis in this manuscript was conducted during his stay at the University of Pennsylvania any opinion expressed in the manuscript does not reflect the view of the Analysis Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Clark, Fu, Liu, Ho, Wang, Lee, Chou, Wang and Tzeng.)

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-β induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca 2+ influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the N -terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.