Concomitant AD and DLB pathologies shape subfield microglia responses in the hippocampus

Hippocampal alteration is at the centre of memory decline in the most common age-related neurodegenerative diseases: Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB). However, the subregional deterioration of the hippocampus differs between both diseases with more severe atrophy in the CA1 subfield of the AD patients. How AD and DLB-typical pathologies compose the various local microenvironment of the hippocampus across AD and DLB needs to be further explored to understand this process. Additionally, microglia responses could further impact the atrophy rate. Some studies suggest that microglia react differently according to the underlying neurodegenerative disorder. How microglia are transformed across hippocampal subfields in AD and DLB, and how their changes are associated with disease-typical pathologies remains to be determined. To these purposes, we performed a volumetric analysis of phospho-Tau (P-Tau), Amyloid-beta (Abeta), and phospho-alpha-Synuclein (P-Syn) loads, quantified and classified microglia according to distinct morphological phenotypes using high-resolution confocal 3D microscopy of hippocampal CA1, CA3 and DG/CA4 subfields of late-onset AD (n=10) and DLB (n=8) as well as age-matched control samples (n=11). We found that each of the Tau, Abeta and Synuclein pathologies followed a specific subregional distribution, relatively preserved across AD and DLB. P-Tau, Abeta and P-Syn burdens were significantly exacerbated in AD, with Tau pathology being particularly severe in the AD CA1. P-Tau and P-Syn burdens were highly correlated across subfields and conditions (R2Spear = 0.79; P < 0.001) and result from a local co-distribution of P-Tau and P-Syn inclusions in neighbouring neurons, with only a low proportion of double-positive cells. In parallel, we assessed the changes of the microglia responses by measuring 16 morphological features of more than 35,000 individual microglial cells and classifying them into seven-distinct morphological clusters. We found microglia features- and clusters-variations subfield- and condition-dependent. Two of the seven morphological clusters, with more amoeboid and less branched forms, were identified as disease-enriched and found to be further increased in AD. Interestingly, some microglial features or clusters were associated with one but more often with a combination of two pathologies in a subfield-dependent manner. In conclusion, our study shows a multimodal association of the hippocampal microglia responses with the co-occurrence, distribution and severity of AD and DLB pathologies. In DLB hippocampi, pathological imprint and microglia responses follow AD trends but with lesser severity. Our study suggests that the increased pathological burdens of P-Tau and P-Syn and associated microglia alterations are involved in a more severe deterioration of the CA1 in AD as compared to DLB.

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Are lysosomes potential therapeutic targets for Parkinson’s disease?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210809123630 ◽

2021 ◽

Vol 20 ◽

Author(s):

A. Petese ◽

V. Cesaroni ◽

S. Cerri ◽

F. Blandini

Keyword(s):

Neurodegenerative Disorder ◽

Association Studies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Genome Wide Association Studies ◽

Lysosomal Dysfunction ◽

Genome Wide ◽

Nigrostriatal Neurons ◽

Disease Modifying Treatment ◽

Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

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Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽

10.1038/s41541-021-00424-2 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Changyoun Kim ◽

Armine Hovakimyan ◽

Karen Zagorski ◽

Tatevik Antonyan ◽

Irina Petrushina ◽

...

Keyword(s):

Dna Vaccines ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Lewy Bodies ◽

Amyloid Β ◽

The Elderly ◽

Brain Regions ◽

Dependent Manner ◽

Lewy Neurites ◽

The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

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(De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants

International Journal of Molecular Sciences ◽

10.3390/ijms222212509 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12509

Author(s):

Joana Angélica Loureiro ◽

Stéphanie Andrade ◽

Lies Goderis ◽

Ruben Gomez-Gutierrez ◽

Claudio Soto ◽

...

Keyword(s):

Secondary Structure ◽

Hydrophobic Interactions ◽

Neurodegenerative Disorder ◽

Sodium Dodecyl ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Cetyltrimethylammonium Chloride ◽

Α Helix ◽

Β Sheet

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils.

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The Triggering Receptor Expressed on Myeloid Cells 2: “TREM-ming” the Inflammatory Component Associated with Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/860959 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Troy T. Rohn

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Senile Plaques ◽

Myeloid Cells ◽

Disease Process ◽

Age Related

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. TREM2 is expressed on microglial cells, the resident macrophages in the CNS, and functions to stimulate phagocytosis on one hand and to suppress cytokine production and inflammation on the other hand. The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS. In this context, an overview of the pathways linking beta-amyloid, neurofibrillary tangles (NFTs), oxidative stress, and inflammation will be discussed.

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Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.690293 ◽

2021 ◽

Vol 13 ◽

Author(s):

Nelson de Oliveira Manzanza ◽

Lucia Sedlackova ◽

Raj N. Kalaria

Keyword(s):

Neurodegenerative Diseases ◽

Lewy Body ◽

Clinical Symptoms ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Lewy Neurites ◽

Post Translational Modifications ◽

Age Related ◽

Neurodegenerative Dementias

Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as the synucleinopathies. LBDs are considered to be among the second most common form of neurodegenerative dementias after Alzheimer's disease. They are progressive conditions with variable clinical symptoms embodied within specific cognitive and behavioral disorders. There are currently no effective treatments for LBDs. LBDs are histopathologically characterized by the presence of abnormal neuronal inclusions commonly known as Lewy Bodies (LBs) and extracellular Lewy Neurites (LNs). The inclusions predominantly comprise aggregates of alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such as aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, and Truncation play important roles in the formation of toxic forms of the protein, which consequently facilitates the formation of these inclusions. This review focuses on the role of different PTMs in aSyn in the pathogenesis of LBDs. We highlight how these PTMs interact with aSyn to promote misfolding and aggregation and interplay with cell membranes leading to the potential functional and pathogenic consequences detected so far, and their involvement in the development of LBDs.

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Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease

10.1101/430603 ◽

2018 ◽

Author(s):

Stephen A. Semick ◽

Rahul A. Bharadwaj ◽

Leonardo Collado-Torres ◽

Ran Tao ◽

Joo Heon Shin ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Brain Regions ◽

Epigenetic Mechanism ◽

Novel Genes ◽

Age Related

AbstractBackgroundLate-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).ResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.ConclusionsThese results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

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Alpha-Synuclein Preserves Mitochondrial Fusion and Function in Neuronal Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4246350 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Gaia Faustini ◽

Elena Marchesan ◽

Laura Zonta ◽

Federica Bono ◽

Emanuela Bottani ◽

...

Keyword(s):

Cortical Neurons ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Physical Interaction ◽

Primary Cortical Neurons ◽

Altered Expression ◽

Extracellular Flux ◽

Mitochondrial Functions ◽

And Function

Dysregulations of mitochondria with alterations in trafficking and morphology of these organelles have been related to Parkinson’s disease (PD), a neurodegenerative disorder characterized by brain accumulation of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-syn) fibrils. Experimental evidence supports that α-syn pathological aggregation can negatively impinge on mitochondrial functions suggesting that this protein may be crucially involved in the control of mitochondrial homeostasis. The aim of this study was to assay this hypothesis by analyzing mitochondrial function and morphology in primary cortical neurons from C57BL/6JOlaHsd α-syn null and C57BL/6J wild-type (wt) mice. Primary cortical neurons from mice lacking α-syn showed decreased respiration capacity measured with a Seahorse XFe24 Extracellular Flux Analyzer. In addition, morphological Airyscan superresolution microscopy showed the presence of fragmented mitochondria while real-time PCR and western blot confirmed altered expression of proteins involved in mitochondrial shape modifications in the primary cortical neurons of α-syn null mice. Transmission electron microscopy (TEM) studies showed that α-syn null neurons exhibited impaired mitochondria-endoplasmic reticulum (ER) physical interaction. Specifically, we identified a decreased number of mitochondria-ER contacts (MERCs) paralleled by a significant increase in ER-mitochondria distance (i.e., MERC length). These findings support that α-syn physiologically preserves mitochondrial functions and homeostasis. Studying α-syn/mitochondria interplay in health and disease is thus pivotal for understanding their involvement in PD and other LB disorders.

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Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

Journal of Parkinson s Disease ◽

10.3233/jpd-202221 ◽

2020 ◽

pp. 1-22

Author(s):

Anne-Marie Castonguay ◽

Claude Gravel ◽

Martin Lévesque

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Passive Immunization ◽

Lewy Bodies ◽

Gene Mutations ◽

Alpha Synuclein ◽

Multiple Sources ◽

Immunization Strategies ◽

A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

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Pesticides and Parkinson’s Disease

The Scientific World JOURNAL ◽

10.1100/tsw.2001.35 ◽

2001 ◽

Vol 1 ◽

pp. 207-208 ◽

Cited By ~ 14

Author(s):

Todd B. Sherer ◽

Ranjita Betarbet ◽

J. Timothy Greenamyre

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Selective Death ◽

Underlying Mechanisms ◽

Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

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C-32 A Neuropsychological Case Study of Very-Late-Onset Psychosis

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acz034.194 ◽

2019 ◽

Vol 34 (6) ◽

pp. 1061-1061

Author(s):

V Sekunda

Keyword(s):

Visual Information ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Demographic History ◽

Lewy Bodies ◽

Long Term Memory ◽

Urine Drug Screen ◽

Impaired Performance ◽

Neuropsychological Profile ◽

Neurocognitive Profile

Abstract Objective Studies have established a relationship between earlier-onset (< 40 years of age) and late-onset (between 40 and 60 years of age) psychosis symptoms on cognitive functioning, but little is known about the neurocognitive profile of very-late-onset psychosis (≥60 years of age) (Sharma et al., 2014; Howard et al., 2000). This case highlights the neuropsychological profile in an older adult with very-late-onset psychosis. Method 84-year-old, right-handed, Caucasian female with no significant medical or psychiatric history prior to 2013. Onset of delusions, paranoia, and tactile, auditory, and visual hallucinations initially beginning in 2013 with no identifiable trigger and worsening symptoms in 2018. Labs within normal limits and urine drug screen was negative. Results Her estimated premorbid verbal functioning fell within the average range which fell slightly below her score as predicted by her demographic history (i.e., education, occupation, region, sex, and race/ethnicity), which fell within the high average range. Her overall objective testing indicated that she demonstrated relative weaknesses encoding increasingly complex auditory and visual information and reliably retrieving the information from her long-term memory on command. She demonstrated intact orientation, impaired performance on a cognitive switching task, and a visuospatial task. Conclusions The patient demonstrated grossly intact performance across many cognitive domains. This paradox highlights the need for further investigation of the neuroanatomical correlates of psychosis in older-adults and its longitudinal neurocognitive profile as often, individuals are presumed to be suffering from a neurodegenerative disorder such as Alzheimer’s type dementia or Dementia with Lewy bodies (Assche et al., 2018).

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