Biochemically-functionalized probes for cell type-specific targeting and recording in the brain DOI Open Access
Anqi Zhang, Theodore J. Zwang, Charles M. Lieber

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 3, 2023

Selective targeting and modulation of distinct cell types neuron subtypes is central to understanding complex neural circuitry, could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh probes, which elicit minimal immune response, with antibodies or peptides markers. Histology studies reveal selective association targeted neurons, astrocytes microglia functionalized probe surfaces without accumulating cells. In vivo chronic electrophysiology further yields recordings consistent these types. Last, probes dopamine 2 receptor expressing neurons show the potential for subtype electrophysiology.

Язык: Английский

Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer’s disease DOI Creative Commons
Zachary Hoglund, Nancy E. Ruiz‐Uribe, Eric del Sastre

и другие.

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Июнь 1, 2024

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component neurofibrillary tangles, can similarly segments. We quantitatively assessed n = 6 Alzheimer's disease (AD), normal aging control brains saw tau-positive vessel segments were present all AD cases. Tau-positive are enriched for at levels higher than surrounding tissue appear to affect arterioles across cortical layers (I-V). Further, isolated these tissues N-terminal phosphorylated T181 T217. Importantly, associated with local areas increased tangles. This suggests accumulation around may reflect clearance failure. sum, data indicate tau, like beta, accumulates exert significant influence vasculature setting AD.

Язык: Английский

Процитировано

8
Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer’s pathology DOI Creative Commons
Theodore J. Zwang, Eric del Sastre,

Nina Wolf

и другие.

Cell Reports, Год журнала: 2024, Номер 43(8), С. 114574 - 114574

Опубликована: Авг. 1, 2024

A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline Alzheimer's disease (AD) because correlate anatomically with areas undergo neuronal loss. We used two-photon longitudinal imaging to directly test this and observed the fate of individual neurons two mouse models. At any time point, without died at >3 times rate as tangles. Additionally, prior dying, they became >20% more distant from neighboring across sessions. Similar microstructural changes were evident population non-tangle-bearing donor tissues. Together, these data suggest nonfibrillar tau puts high risk death, surprisingly, presence tangle reduces risk. Moreover, cortical microstructure appear be better predictor imminent cell death than status promising tool for identifying dying Alzheimer's.

Язык: Английский

Процитировано

5
Biochemically functionalized probes for cell-type–specific targeting and recording in the brain DOI Creative Commons
Anqi Zhang, Theodore J. Zwang, Charles M. Lieber

и другие.

Science Advances, Год журнала: 2023, Номер 9(48)

Опубликована: Ноя. 29, 2023

Selective targeting and modulation of distinct cell types neuron subtypes is central to understanding complex neural circuitry could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh probes, which elicit minimal immune response, with antibodies or peptides markers. Histology studies reveal selective association targeted neurons, astrocytes, microglia functionalized probe surfaces without accumulating cells. In vivo chronic electrophysiology further yields recordings consistent these types. Last, probes dopamine receptor 2 expressing neurons show the potential for neuron-subtype–specific electrophysiology.

Язык: Английский

Процитировано

10
The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer’s Disease DOI Open Access
Karthikeyan Tangavelou, Kiran Bhaskar

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12335 - 12335

Опубликована: Ноя. 17, 2024

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S macroautophagy, aggrephagy. Neurofibrillary tangles (NFTs) form upon impairment of aggrephagy, eventually, ubiquitin chaperone valosin-containing protein (VCP) heat shock 70 kDa (HSP70) are recruited sites NFTs for extraction ubiquitin-proteasome system (UPS)-mediated degradation. However, degradation in neurons allows be secreted into extracellular space. Secreted can monomers, oligomers, paired helical filaments (PHFs), which seeding competent pathological that endocytosed/phagocytosed healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes, often causing proteotoxic stress eventually triggers senescence. Senescent secrete senescence-associated secretory phenotype (SASP) factors, trigger cellular atrophy, decreased brain volume human AD. molecular mechanisms senescence not entirely understood an emerging area research. Therefore, this comprehensive review summarizes pertinent studies provided evidence sequential degradation, failure, mechanistic link between tau-driven

Язык: Английский

Процитировано

2
Brain Vasculature Accumulates Tau and Is Spatially Related to Tau Tangle Pathology in Alzheimer’s Disease DOI Creative Commons
Zachary Hoglund, Nancy E. Ruiz‐Uribe, Eric del Sastre

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 28, 2024

Abstract Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting homeostasis. In this work we provide new evidence from three-dimensional human brain histology that tau protein, the main component neurofibrillary tangles, can similarly segments. We quantitatively assessed n=6 Alzheimer’s disease (AD), normal aging control brains saw tau-positive vessel segments were present all AD cases. Tau-positive are enriched for at levels higher than surrounding tissue appear to affect arterioles across cortical layers (I-V). Further, isolated these tissues N-terminal phosphorylated T181 T217. Importantly, associated with local areas increased tangles. This suggests accumulation around may reflect clearance failure. sum, data indicate tau, like beta, accumulates exert significant influence vasculature setting AD.

Язык: Английский

Процитировано

1
The contribution of oligodendrocytes to amyloid and tau pathologies in mouse models of Alzheimer’s disease DOI
Andrew Octavian Sasmita

Опубликована: Янв. 1, 2024

Oligodendrocytes (OLs) are the myelinating glia of CNS and capable metabolically supporting long axonal projections by providing local fuel production. OL myelin health, however, start degrading around second half human life, which coincides with predicted age at Alzheimer's disease (AD), a debilitating neurodegenerative disease, may begin to develop. Although AD is often considered gray matter, or neurons be exact, recent evidence has indicated involvement glial cells in its pathophysiology. Earlier work shown that dysfunctional risk factor for amyloid-β (Aβ) plaque burden, one hallmarks AD. Thus, general aim this thesis expand our current understanding role context In Chapter I, we investigated whether OLs, alongside excitatory (ExNs), can generate Aβ vivo. We first generated genetically modified mouse models amyloidosis cell-type specific ablation β-secretase 1 (BACE1), key enzyme By combining quantitative light-sheet microscopy (LSM), 2D imaging, vitro cultures, sensitive electrochemiluminescence assay, report novel data showing OLs contribute burden vivo, especially white matter regions where predominate. ExNs, remain primary contributor Interestingly, genetic deletion BACE1 cortical hippocampal ExNs resulted major reductions subcortical burden. This suggests processing occur fibers originating from forebrain projecting into structures, would then released. analyzing several chapter, propose deposition requires reaching threshold concentration, without ExN contribution, concentration initially insufficient induce seeding. Together, findings chapter potentially advance knowledge on seeding growth kinetics, further allow us consider as viable target anti-amyloid therapies such inhibitors. The objective II was previous study linking amyloid pathology turning focus tau pathology. precedes tau, still known executioner neuronal cell death performed imaging battery behavioral tests model tauopathy, inducing acute dysmyelination separate cohorts. discovered damage heightened both experimental cases, stronger effect seen due dysmyelination. Worsening also correlated outcomes: Mice were much slower than control animal, experienced additive motor impairments evident anxiety reduction defects cognitive processing. sum, preliminarily suggest leads worsen Finally, III, potential cause large discrepancies utilizing LSM labeled hemibrains 5xFAD mice, observed transgenic inheritance pattern modulated load after age- sex-matching. inherited their transgenes paternal source developed significantly greater maternal counterparts. previously unreported unlikely result immune priming instead, likely epigenetic modulation transgene itself. Our could thus support conduct more reproducible experiments field animal research. conclusion, indicates serve contributory roles thought, terms pathologies. missing link production accumulation, opening up new avenues research pathophysiology development strategies address pathogenesis.

Язык: Английский

Процитировано

0
Biochemically-functionalized probes for cell type-specific targeting and recording in the brain DOI Open Access
Anqi Zhang, Theodore J. Zwang, Charles M. Lieber

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 3, 2023

Selective targeting and modulation of distinct cell types neuron subtypes is central to understanding complex neural circuitry, could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh probes, which elicit minimal immune response, with antibodies or peptides markers. Histology studies reveal selective association targeted neurons, astrocytes microglia functionalized probe surfaces without accumulating cells. In vivo chronic electrophysiology further yields recordings consistent these types. Last, probes dopamine 2 receptor expressing neurons show the potential for subtype electrophysiology.

Язык: Английский

Процитировано

0