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Contribution of the serotonergic system to developmental brain abnormalities in autism spectrum disorder

Wegiel, Jarek; Chadman, Kathryn; London, Eric; Wisniewski, Thomas; Wegiel, Jerzy
This review highlights a key role of the serotonergic system in brain development and in distortions of normal brain development in early stages of fetal life resulting in cascades of abnormalities, including defects of neurogenesis, neuronal migration, neuronal growth, differentiation, and arborization, as well as defective neuronal circuit formation in the cortex, subcortical structures, brainstem, and cerebellum of autistic subjects. In autism, defects in regulation of neuronal growth are the most frequent and ubiquitous developmental changes associated with impaired neuron differentiation, smaller size, distorted shape, loss of spatial orientation, and distortion of cortex organization. Common developmental defects of the brain in autism include multiregional focal dysplastic changes contributing to local neuronal circuit distortion, epileptogenic activity, and epilepsy. There is a discrepancy between more than 500 reports demonstrating the contribution of the serotonergic system to autism's behavioral anomalies, highlighted by lack of studies of autistic subjects' brainstem raphe nuclei, the center of brain serotonergic innervation, and of the contribution of the serotonergic system to the diagnostic features of autism spectrum disorder (ASD). Discovery of severe fetal brainstem auditory system neuronal deficits and other anomalies leading to a spectrum of hearing deficits contributing to a cascade of behavioral alterations, including deficits of social and verbal communication in individuals with autism, is another argument to intensify postmortem studies of the type and topography of, and the severity of developmental defects in raphe nuclei and their contribution to abnormal brain development and to the broad spectrum of functional deficits and comorbid conditions in ASD.
PMID: 38500252
ISSN: 1939-3806
CID: 5640252

Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease

Wang, Ping; Lynn, Audrey; Miskimen, Kristy; Song, Yeunjoo E; Wisniewski, Thomas; Cohen, Mark; Appleby, Brian S; Safar, Jiri G; Haines, Jonathan L
INTRODUCTION/BACKGROUND:Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS:Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS:). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.
PMID: 38184787
ISSN: 1552-5279
CID: 5639682

Down Syndrome Biobank Consortium: A perspective

Aldecoa, Iban; Barroeta, Isabel; Carroll, Steven L; Fortea, Juan; Gilmore, Anah; Ginsberg, Stephen D; Guzman, Samuel J; Hamlett, Eric D; Head, Elizabeth; Perez, Sylvia E; Potter, Huntington; Molina-Porcel, Laura; Raha-Chowdhury, Ruma; Wisniewski, Thomas; Yong, William H; Zaman, Shahid; Ghosh, Sujay; Mufson, Elliott J; Granholm, Ann-Charlotte
Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type dementia by early midlife. Despite ongoing clinical trials to treat late-onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not available. Of the genetic causes of AD, people with DS represent the largest cohort. Currently, there is a knowledge gap regarding the underlying neurobiological mechanisms of DS-related AD (DS-AD), partly due to limited access to well-characterized brain tissue and biomaterials for research. To address this challenge, we created an international consortium of brain banks focused on collecting and disseminating brain tissue from persons with DS throughout their lifespan, named the Down Syndrome Biobank Consortium (DSBC) consisting of 11 biobanking sites located in Europe, India, and the USA. This perspective describes the DSBC harmonized protocols and tissue dissemination goals.
PMID: 38270275
ISSN: 1552-5279
CID: 5625192

Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy

Walker, Jamie M; Orr, Miranda E; Orr, Timothy C; Thorn, Emma L; Christie, Thomas D; Yokoda, Raquel T; Vij, Meenakshi; Ehrenberg, Alexander J; Marx, Gabriel A; McKenzie, Andrew T; Kauffman, Justin; Selmanovic, Enna; Wisniewski, Thomas; Drummond, Eleanor; White, Charles L; Crary, John F; Farrell, Kurt; Kautz, Tiffany F; Daoud, Elena V; Richardson, Timothy E
INTRODUCTION/BACKGROUND:Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS:Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS:Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION/CONCLUSIONS:These results suggest subfield-specific proteome differences that may explain some of the differences in Aβ and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aβ in the pathologic process. HIGHLIGHTS/CONCLUSIONS:Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aβ in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.
PMID: 37777848
ISSN: 1552-5279
CID: 5633692

Similar brain proteomic signatures in Alzheimer's disease and epilepsy

Leitner, Dominique; Pires, Geoffrey; Kavanagh, Tomas; Kanshin, Evgeny; Askenazi, Manor; Ueberheide, Beatrix; Devinsky, Orrin; Wisniewski, Thomas; Drummond, Eleanor
The prevalence of epilepsy is increased among Alzheimer's Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau expression. This suggests that tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. Our results provide insights into common mechanisms in epilepsy and AD and highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD.
PMCID:10827928
PMID: 38289539
ISSN: 1432-0533
CID: 5627492

Mitochondria in Alzheimer's Disease Pathogenesis

Reiss, Allison B; Gulkarov, Shelly; Jacob, Benna; Srivastava, Ankita; Pinkhasov, Aaron; Gomolin, Irving H; Stecker, Mark M; Wisniewski, Thomas; De Leon, Joshua
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.
PMCID:10890468
PMID: 38398707
ISSN: 2075-1729
CID: 5634602

Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease

Wang, Ping; Lynn, Audrey; Miskimen, Kristy; Song, Yeunjoo E.; Wisniewski, Thomas; Cohen, Mark; Appleby, Brian S.; Safar, Jiri G.; Haines, Jonathan L.
INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10−8) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10−5). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.
SCOPUS:85181514299
ISSN: 1552-5260
CID: 5630242

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Peltier, Morgan R; Behbodikhah, Jennifer; Renna, Heather A; Ahmed, Saba; Srivastava, Ankita; Arita, Yuko; Kasselman, Lora J; Pinkhasov, Aaron; Wisniewski, Thomas; De Leon, Joshua; Reiss, Allison B
Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.
PMID: 37864505
ISSN: 1708-8267
CID: 5612952

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

Rozalem Aranha, Mateus; Iulita, Maria Florencia; Montal, Victor; Pegueroles, Jordi; Bejanin, Alexandre; Vaqué-Alcázar, Lídia; Grothe, Michel J; Carmona-Iragui, Maria; Videla, Laura; Benejam, Bessy; Arranz, Javier; Padilla, Concepción; Valldeneu, Sílvia; Barroeta, Isabel; Altuna, Miren; Fernández, Susana; Ribas, Laia; Valle-Tamayo, Natalia; Alcolea, Daniel; González-Ortiz, Sofía; Bargalló, Núria; Zetterberg, Henrik; Blennow, Kaj; Blesa, Rafael; Wisniewski, Thomas; Busciglio, Jorge; Cuello, A Claudio; Lleó, Alberto; Fortea, Juan
BACKGROUND:Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. METHODS:We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. RESULTS:In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. DISCUSSION/CONCLUSIONS:BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.
PMID: 37021589
ISSN: 1552-5279
CID: 5463832

FDA-approved carbonic anhydrase inhibitors reduce amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness

Canepa, Elisa; Parodi-Rullan, Rebecca; Vazquez-Torres, Rafael; Gamallo-Lana, Begona; Guzman-Hernandez, Roberto; Lemon, Nicole L; Angiulli, Federica; Debure, Ludovic; Ilies, Marc A; Østergaard, Leif; Wisniewski, Thomas; Gutiérrez-Jiménez, Eugenio; Mar, Adam C; Fossati, Silvia
INTRODUCTION/BACKGROUND:Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. METHODS:Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness. RESULTS:Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis. DISCUSSION/CONCLUSIONS:This work substantiates the potential application of CAIs in clinical trials for AD and CAA.
PMID: 37186121
ISSN: 1552-5279
CID: 5544132