Dataset Information

Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

SUBMITTER: Armijo E

PROVIDER: S-EPMC8303262 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer's Disease.

Armijo Enrique E Edwards George G Flores Andrea A Vera Jorge J Shahnawaz Mohammad M Moda Fabio F Gonzalez Cesar C Sanhueza Magdalena M Soto Claudio C

Cells 20210716 7

Alzheimer's disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms ...[more]

PMID: 34359972

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Project description:BACKGROUND:Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (A?) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and A? soluble oligomers, which contain extensive ?-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-?-sheet conformation antibody (a?ComAb), to selectively recognize pathological A? and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9. METHODS:In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18-22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks. RESULTS:Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p?<?0.05). Furthermore, ELISA using oligomeric and monomeric A? showed a preferential affinity for oligomeric A?. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p?<?0.01) and A? (p?<?0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p?<?0.01) and Barnes maze performance (p?=?0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p?<?0.05), and there was a trend for a reduction in soluble A? levels in the brain homogenates of female 3xTg-AD mice (p?=?0.06). CONCLUSIONS:This study shows that acute treatment with an a?ComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.

Project description:A synaptic theory of Working Memory (WM) has been developed in the last decade as a possible alternative to the persistent spiking paradigm. In this context, we have developed a neural mass model able to reproduce exactly the dynamics of heterogeneous spiking neural networks encompassing realistic cellular mechanisms for short-term synaptic plasticity. This population model reproduces the macroscopic dynamics of the network in terms of the firing rate and the mean membrane potential. The latter quantity allows us to gain insight of the Local Field Potential and electroencephalographic signals measured during WM tasks to characterize the brain activity. More specifically synaptic facilitation and depression integrate each other to efficiently mimic WM operations via either synaptic reactivation or persistent activity. Memory access and loading are related to stimulus-locked transient oscillations followed by a steady-state activity in the β-γ band, thus resembling what is observed in the cortex during vibrotactile stimuli in humans and object recognition in monkeys. Memory juggling and competition emerge already by loading only two items. However more items can be stored in WM by considering neural architectures composed of multiple excitatory populations and a common inhibitory pool. Memory capacity depends strongly on the presentation rate of the items and it maximizes for an optimal frequency range. In particular we provide an analytic expression for the maximal memory capacity. Furthermore, the mean membrane potential turns out to be a suitable proxy to measure the memory load, analogously to event driven potentials in experiments on humans. Finally we show that the γ power increases with the number of loaded items, as reported in many experiments, while θ and β power reveal non monotonic behaviours. In particular, β and γ rhythms are crucially sustained by the inhibitory activity, while the θ rhythm is controlled by excitatory synapses.

Dataset Information

Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer's Disease.

Publications

Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer's Disease.

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