Dataset Information

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

ABSTRACT: With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress.

SUBMITTER: AbdAlla S

PROVIDER: S-EPMC4677170 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

AbdAlla Said S El Hakim Ahmed A Abdelbaset Ahmed A Elfaramawy Yasser Y Quitterer Ursula U

BioMed research international 20151130

With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment ...[more]

PMID: 26697495

Similar Datasets

Project description:BACKGROUND:Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS:Hypertensive male rats (n?=?13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n?=?5). RESULTS:Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p?=?.018) and white matter (corpus callosum: p?=?.016; external capsule: p?=?.049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p?=?.005; hippocampus: p?<?.001; corpus callosum: p?=?.001; external capsule: p?<?.001) and a significant drop in cortical oxygen levels (p?<?.05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p?=?.008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p?=?.013), p-Tau (pThr231) in dorsolateral cortex (p?=?.011) and hippocampus (p?=?.003), active interleukin-1? (p?<?.001) and neurodegeneration (dorsolateral cortex: p?=?.043, hippocampus: p?=?.044). Human patients with subcortical ischemic vascular disease, a type of vascular dementia (n?=?38; mean age?=?68; male/female ratio?=?23/15) showed reduced hippocampal volumes and cortical shrinking (p?<?.05) consistent with the neuronal cell death observed in our hypertensive rat model as compared to healthy controls (n?=?47; mean age?=?63; male/female ratio?=?18/29). CONCLUSIONS:Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patient brain atrophy, which is relevant to vascular disease.

Dataset Information

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

Publications

Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure