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Authors: Ahmed, Heba A. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, …with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications. Objective: To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging. Methods: Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months. Results: Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice. Conclusion: Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals. Show more

Keywords: Angiotensin receptor blocker, candesartan, cognitive impairment, oxidative stress, sporadic Alzheimer’s disease

DOI: 10.3233/ADR-220016

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 257-269, 2022

Authors: Nasoohi, Sanaz | Parveen, Kehkashan | Ishrat, Tauheed

Article Type: Review Article

Abstract: Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer’s disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating “toxic metabolites” emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or “type 3 diabetes”. Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including …those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia. Show more

Keywords: Alzheimer’s disease, brain insulin resistance, inflammasomes, metabolic syndrome, oxidative stress, thioredoxin-interacting protein (TXNIP), type 3 diabetes

DOI: 10.3233/JAD-180735

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 857-885, 2018

Authors: Li, Lexiao | Ismael, Saifudeen | Nasoohi, Sanaz | Sakata, Kazuko | Liao, Francesca-Fang | McDonald, Michael P. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison …with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias. Show more

Keywords: Alzheimer’s disease, amyloid plaques, hyperphosphorylated tau, NLRP3 inflammasome interlukin-1, thioredoxin-interacting protein

DOI: 10.3233/JAD-180814

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 255-265, 2019

Authors: Ismael, Saifudeen | Mirzahosseini, Golnoush | Ahmed, Heba A. | Yoo, Arum | Kassan, Modar | Malik, Kafait U. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Background: Understanding Alzheimer’s disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD. Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals. Methods: We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in comparison with age-matched non-demented …controls. Results: The expression of AT1 R increased in the hippocampus, whereas AT2 R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus. Conclusion: The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1 R and AT2 R pathways may lead to novel therapies for the management of AD. Show more

Keywords: Alzheimer’s disease, angiotensin-converting enzyme, angiotensin type 1 receptor, angiotensin type 2 receptor, renin-angiotensin system

DOI: 10.3233/JAD-215051

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1473-1484, 2021