Generation of a human induced pluripotent stem cell–based model for tauopathies combining three microtubule‐associated protein TAU mutations which displays several phenotypes linked to neurodegeneration

Lam

et al. 2018

Preprint

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer's disease and other dementias, yet the physiological state of tau molecules within cells remains unclear. Using single molecule imaging, we directly observe that the microtubule lattice regulates reversible tau selfassociation, leading to dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of MT severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, controlled by the microtubule, is an important mechanism of tau's biological functions, and that oligomerization of tau is a common property shared between the physiological and disease forms of the molecule.

supporting

confidence: 79%

Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Lam

et al. 2018

Preprint

“…From the published literature, studies performing MEA experiments using primary cultures of rodent cortical neurons have a range of reported age of cultures: DIV post plating from dissected brain, and the time of analysis ranges from DIV7 to DIV35, although DIV14 -DIV28 is most common (Table 2). Conversely, studies that instead used neuronal cultures derived from stem cells have a range of culture ages differing to a greater degree, over 30 d (DeRosa et al, 2018;Russo et al, 2018), including up to DIV70 (García-León et al, 2018). This broad range is expected given the variety of differentiation protocols used and increased interval until these cells become electrically active.…”

Section: Changes In Spontaneous Firing Across Arrays With Culture Matmentioning

confidence: 99%

Assessment of Spontaneous Neuronal ActivityIn VitroUsing Multi-Well Multi-Electrode Arrays: Implications for Assay Development

Negri

Menon

Young‐Pearse

2020

eNeuro

Multi-electrode arrays (MEAs) are being more widely used by researchers as an instrument platform for monitoring prolonged, non-destructive recordings of spontaneously firing neurons in vitro for applications in modeling Alzheimer's, Parkinson's, schizophrenia, and many other diseases of the human CNS. With the more widespread use of these instruments, there is a need to examine the prior art of studies utilizing MEAs and delineate best practices for data acquisition and analysis to avoid errors in interpretation of the resultant data. Using a dataset of recordings from primary rat (Rattus norvegicus) cortical cultures, methods and statistical power for discerning changes in neuronal activity on the array level are examined. Further, a method for unsupervised spike sorting is implemented, allowing for the resolution of action potential incidents down to the single neuron level. Following implementation of spike sorting, the dynamics of firing frequency across populations of individual neurons and networks are examined longitudinally. Finally, the ability to detect a frequency independent phenotype, the change in action potential amplitude, is demonstrated through the use of pore-forming neurotoxin treatments. Taken together, this study provides guidance and tools for users wishing to incorporate multi-well MEA usage into their studies.

“…Upregulation of tau was coupled with enhanced stress-inducible markers and vulnerability of cells to proteotoxic, excitotoxic, and mitochondrial stressors [43]. iPSCs with MAPT mutations N279K, P301L, and E10 + 16 had neuritis outgrowth deficiencies [44]. The iPSCs were prepared separately, and their phenotypes manifested accumulations of tau protein, mitochondrial dysfunction, and defects of nerve growth and differentiation [45].…”

Section: Microtubule-associated Protein Tau Gene Mutationmentioning

confidence: 99%

“…Deficiencies in neurite outgrowth and upregulation of neurodegenerative pathways Juan Antonio García-León [44] 3. γ-secretase Inhibitors and γ-Secretase Modulators Mutations in the PSEN-1 gene account for approximately 50% of the pathogenesis of early onset of AD and are the most common gene mutations in this disease [47]. Although gene mutations are responsible for early onset of AD, 95% of AD cases are late-onset diseases and are not necessarily caused by genetic mutations [48].…”

Section: Gene Mutation Of Ipscs Ips Cells Produce Effect Referencesmentioning

confidence: 99%

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer’s Disease

Wuli

Tsai

Chiou

et al. 2020

IJMS

Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques composed of the β-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of β-amyloid in the brain, such as gamma secretase (γ-secretase). Induced pluripotent stem cells from patients with Alzheimer’s disease with different underlying genetic mechanisms may help model different phenotypes of Alzheimer’s disease and facilitate personalized drug screening platforms for the identification of small molecules. We also discuss recent developments by γ-secretase inhibitors and modulators in the treatment of AD. In addition, small-molecule drugs isolated from Chinese herbal medicines have been shown effective in treating Alzheimer’s disease. We propose a mechanism of small-molecule drugs in treating Alzheimer’s disease. Combining therapy with different small-molecule drugs may increase the chance of symptomatic treatment. A customized strategy tailored to individuals and in combination with therapy may be a more suitable treatment option for Alzheimer’s disease in the future.