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      Stem Cell Therapies in Alzheimer’s Disease: Applications for Disease Modeling

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      Journal of Pharmacology and Experimental Therapeutics
      American Society for Pharmacology & Experimental Therapeutics (ASPET)

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          The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease

          Hampel et al. review the role of the cholinergic system in cognition and how cholinergic deficits in Alzheimer’s disease interact with other aspects of disease pathophysiology. They document the benefits of cholinergic therapies at various stages of disease, and argue that the weight of the evidence confirms their continued value. Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain’s cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer’s disease. The cholinergic hypothesis of Alzheimer’s disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer’s disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer’s disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer’s disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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            Diagnosis and Management of Dementia: Review

            Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the US, Alzheimer’s disease (AD) affects 5.8 million people. However, dementia is commonly associated with more than one neuropathology, usually AD with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a moderately extended mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (e.g., symptoms present, but normal examination), neuropsychological testing can help with a diagnosis. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing should be considered in atypical dementia cases, such as age of onset under 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients benefit from non-pharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For AD, this includes an acetylcholinesterase inhibitor such as donepezil for mild-to-severe dementia, and memantine (used alone or as an add-on therapy) for moderate-to-severe dementia. Rivastigmine is approved for the symptomatic treatment of Parkinson’s disease dementia. AD currently affects 5.8 million persons in the US, and is a common cause of dementia which is usually accompanied by other neuropathology. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both non-pharmacologic and pharmacologic approaches.
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              APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types

              The apolipoprotein E4 ( APOE4 ) variant is the single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD). However, the cell type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes) and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ 42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell type-specific changes associated with the APOE4 variant.
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                Author and article information

                Journal
                Journal of Pharmacology and Experimental Therapeutics
                J Pharmacol Exp Ther
                American Society for Pharmacology & Experimental Therapeutics (ASPET)
                0022-3565
                1521-0103
                April 07 2021
                May 2021
                May 2021
                February 08 2021
                : 377
                : 2
                : 207-217
                Article
                10.1124/jpet.120.000324
                33558427
                f0706424-720d-47fa-a1ff-caee0453d0f7
                © 2021
                History

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