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Article ; Online: Astrocytic apoE4 and tau: Deadly combination for neurons.

Chakrabarty, Paramita / Borchelt, David R

Cell reports. Medicine

2021 Volume 2, Issue 6, Page(s) 100316

Abstract: New data from Wang and ... ...

Abstract	New data from Wang and colleagues
MeSH term(s)	Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Astrocytes ; Humans ; Neurons ; tau Proteins/genetics
Chemical Substances	Apolipoprotein E4 ; tau Proteins
Language	English
Publishing date	2021-06-15
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2021.100316
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Article: Hyperacetylation mimetics within the tau filament core inhibits prion-like propagation of misfolded tau.

Smith, Ethan D / McKenna, Robert / Mietzsch, Mario / Borchelt, David R / Prokop, Stefan / Chakrabarty, Paramita

bioRxiv : the preprint server for biology

2024

Abstract: Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP) ...

Abstract	Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). This has led to the idea that acetylation influences tau aggregation. Using a HEK293 cell-based aggregation assay, we tested whether acetylation-mimicking substitutions (K→Q) on five AD-associated acetyl-modified sites (AcK-311, 353, 369, 370, 375) influenced its propensity to aggregate when exposed to tau seeds derived from two clinically distinctive diseases - AD and PSP. In combination, the presence of 5K→Q sites ablated tau aggregation induced by seeds from both AD and PSP patients, indicating that acetylation within the filament core domain of tau could have an inhibitory effect on seed-mediated aggregation. We had previously identified that a phosphorylation-mimetic on Ser305 (S→E) abrogated tau aggregation by seeds from AD patients, without affecting seeding by PSP patients. Combining the S305→E to the 5K→Q acetyl-modified sites, we found that this tau could now be seeded only by PSP patients, but not by AD patients, confirming Ser305 as a critical determinant of strain-specific tau seeding. On the other hand, acetylation-nullifying substitutions (K→R or K→A) on these same Lys sites did not alter tau seeding abilities compared to the parental tau construct. Notably, the combined acetylation-nullifying Alanine substitutions on these 5 Lys sites resulted in spontaneous self-aggregation, with the filaments resembling amorphous deposits. All together, we demonstrate that cooperative acetyl-occupancy in the tau filament core influences seeded propagation of misfolded tau as well as drives self-aggregation.
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.12.589253
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Article ; Online: Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis.

McFarland, Karen N / Chakrabarty, Paramita

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2022 Volume 19, Issue 1, Page(s) 186–208

Abstract: Immune activation accompanies the development of proteinopathy in the brains of Alzheimer's dementia patients. Evolving from the long-held viewpoint that immune activation triggers the pathological trajectory in Alzheimer's disease, there is accumulating ...

Abstract	Immune activation accompanies the development of proteinopathy in the brains of Alzheimer's dementia patients. Evolving from the long-held viewpoint that immune activation triggers the pathological trajectory in Alzheimer's disease, there is accumulating evidence now that microglial activation is neither pro-amyloidogenic nor just a simple reactive process to the proteinopathy. Preclinical studies highlight an interesting aspect of immunity, i.e., spurring immune system activity may be beneficial under certain circumstances. Indeed, a dynamic evolving relationship between different activation states of the immune system and its neuronal neighbors is thought to regulate overall brain organ health in both healthy aging and progression of Alzheimer's dementia. A new premise evolving from genome, transcriptome, and proteome data is that there might be at least two major phases of immune activation that accompany the pathological trajectory in Alzheimer's disease. Though activation on a chronic scale will certainly lead to neurodegeneration, this emerging knowledge of a potential beneficial aspect of immune activation allows us to form holistic insights into when, where, and how much immune system activity would need to be tuned to impact the Alzheimer's neurodegenerative cascade. Even with the trove of recently emerging -omics data from patients and preclinical models, how microglial phenotypes are functionally related to the transition of a healthy aging brain towards progressive degenerative state remains unknown. A deeper understanding of the synergism between microglial functional states and brain organ health could help us discover newer interventions and therapies that enable us to address the current paucity of disease-modifying therapies in Alzheimer's disease.
MeSH term(s)	Alzheimer Disease/pathology ; Brain/pathology ; Homeostasis ; Humans ; Microglia/pathology ; Neurons/pathology
Language	English
Publishing date	2022-03-14
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-021-01179-3
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Article: Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity.

Koller, Emily J / Chakrabarty, Paramita

Frontiers in molecular neuroscience

2020 Volume 13, Page(s) 151

Abstract: The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during ... ...

Abstract	The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during normal aging, in neurodegenerative diseases such as Alzheimer's disease (AD), this loss is accelerated dramatically, leading to the incapacitation of patients within a decade of onset of cognitive symptoms. The mechanisms that underlie this accelerated loss of neuroplasticity in AD are still not completely understood. While the progressively increasing proteinopathy burden, such as amyloid β (Aβ) plaques and tau tangles, definitely contribute directly to a neuron's functional demise, the role of non-neuronal cells in controlling neuroplasticity is slowly being recognized as another major factor. These non-neuronal cells include astrocytes, microglia, and oligodendrocytes, which through regulating brain homeostasis, structural stability, and trophic support, play a key role in maintaining normal functioning and resilience of the neuronal network. It is believed that chronic signaling from these cells affects the homeostatic network of neuronal and non-neuronal cells to an extent to destabilize this harmonious milieu in neurodegenerative diseases like AD. Here, we will examine the experimental evidence regarding the direct and indirect pathways through which astrocytes and microglia can alter brain plasticity in AD, specifically as they relate to the development and progression of tauopathy. In this review article, we describe the concepts of neuroplasticity and glial plasticity in healthy aging, delineate possible mechanisms underlying tau-induced plasticity dysfunction, and discuss current clinical trials as well as future disease-modifying approaches.
Language	English
Publishing date	2020-08-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2020.00151
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Article ; Online: Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau.

Smith, Ethan D / Vo, Quan / Giasson, Benoit I / Borchelt, David R / Prokop, Stefan / Chakrabarty, Paramita

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 172

Abstract: Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights ...

Abstract	Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.
MeSH term(s)	Humans ; tau Proteins/metabolism ; Phosphorylation ; Detergents ; Tauopathies/genetics ; Tauopathies/metabolism ; Alzheimer Disease/metabolism
Chemical Substances	tau Proteins ; Detergents
Language	English
Publishing date	2023-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01664-0
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Article ; Online: A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms.

Park, Gwoncheol / Kadyan, Saurabh / Hochuli, Nathaniel / Pollak, Julie / Wang, Bo / Salazar, Gloria / Chakrabarty, Paramita / Efron, Philip / Sheffler, Julia / Nagpal, Ravinder

Gut microbes

2024 Volume 16, Issue 1, Page(s) 2323752

Abstract: Alzheimer's disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a ...

Abstract	Alzheimer's disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a modified Mediterranean-ketogenic diet (MkD) on AD-related neurocognitive pathophysiology and underlying mechanisms related to the gut-microbiome-brain axis. The findings revealed that MkD induces profound shifts in the gut microbiome community and microbial metabolites. Most notably, MkD promoted growth of the
MeSH term(s)	Animals ; Mice ; Gastrointestinal Microbiome ; Brain ; Diet, Mediterranean ; Microbiota ; Brain-Gut Axis ; Alzheimer Disease
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2575755-6
ISSN	1949-0984 ; 1949-0984
ISSN (online)	1949-0984
ISSN	1949-0984
DOI	10.1080/19490976.2024.2323752
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Article ; Online: Therapeutic approaches targeting Apolipoprotein E function in Alzheimer's disease.

Williams, Tosha / Borchelt, David R / Chakrabarty, Paramita

Molecular neurodegeneration

2020 Volume 15, Issue 1, Page(s) 8

Abstract: One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular ... ...

Abstract	One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Genetic Predisposition to Disease/genetics ; Humans
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2020-01-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-020-0358-9
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Article ; Online: α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

Sorrentino, Zachary A / Giasson, Benoit I / Chakrabarty, Paramita

Acta neuropathologica

2019 Volume 138, Issue 1, Page(s) 1–21

Abstract: α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of ... ...

Abstract	α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteostasis in immune cells is a major area of research that can have far-reaching implications for future immunobiotherapies in α-synucleinopathies. Accumulation of aggregated α-synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in α-synucleinopathies through various pathways. Here, we summarize our current knowledge on how astrocytic α-synucleinopathy affects CNS function in health and disease and propose a model of neuroglial connectome altered by α-synuclein proteostasis that might be amenable to immune-based therapies.
MeSH term(s)	Animals ; Astrocytes/pathology ; Homeostasis/physiology ; Humans ; Lewy Body Disease/metabolism ; Lewy Body Disease/pathology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurons/pathology ; alpha-Synuclein/metabolism
Chemical Substances	alpha-Synuclein
Language	English
Publishing date	2019-02-23
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-019-01977-2
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Article ; Online: Author Correction: IL-10 based immunomodulation initiated at birth extends lifespan in a familial mouse model of amyotrophic lateral sclerosis.

Strickland, Michael R / Ibanez, Kristen R / Yaroshenko, Mariya / Diaz, Carolina Ceballos / Borchelt, David R / Chakrabarty, Paramita

Scientific reports

2021 Volume 11, Issue 1, Page(s) 3396

Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-83092-5
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Article ; Online: Gut mycobiome dysbiosis after sepsis and trauma.

Park, Gwoncheol / Munley, Jennifer A / Kelly, Lauren S / Kannan, Kolenkode B / Mankowski, Robert T / Sharma, Ashish / Upchurch, Gilbert / Casadesus, Gemma / Chakrabarty, Paramita / Wallet, Shannon M / Maile, Robert / Bible, Letitia E / Wang, Bo / Moldawer, Lyle L / Mohr, Alicia M / Efron, Philip A / Nagpal, Ravinder

Critical care (London, England)

2024 Volume 28, Issue 1, Page(s) 18

Abstract: Background: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical ... ...

Abstract	Background: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. Methods: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. Results: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. Conclusions: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.
MeSH term(s)	Humans ; Mycobiome ; Dysbiosis/complications ; Dysbiosis/microbiology ; Gastrointestinal Microbiome ; Candida ; Bacteria ; Sepsis/complications ; Fungi
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2041406-7
ISSN	1466-609X ; 1364-8535
ISSN (online)	1466-609X
ISSN	1364-8535
DOI	10.1186/s13054-023-04780-4
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