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

Said Abdalla,Yasser Elfaramawy,Ahmed Abdelbaset,Ahmed El Hakim,Ursula Quitterer

doi:10.1155/2015/917156

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia
Because the angiotensinconverting enzyme (ACE) is upregulated in brains of AD patients and mice [20], we asked for an interrelationship between angiotensin-converting enzyme (Ace) and stress
We used the chronic unpredictable mild stress model to investigate the role of Ace in stressinduced signs of neurodegeneration

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia. While genetic factors are causally linked to familial AD, the pathogenesis of the predominant late-onset sporadic AD is diverse and less defined. Age is one of the bestdocumented risk factors for sporadic AD, which acts in concert with a wide array of brain insult-promoting vascular and metabolic factors such as hypertension, ischemia, diabetes, high cholesterol, and different forms of environmental stress and stress-related psychiatric symptoms, that is, depression and anxiety [1,2,3]. Experimental models of AD often reproduce genetic alterations whereas the impact of additional brain-damaging factors is more difficult to assess. The chronic unpredictable mild stress (CUMS) model imitates psychiatric risk factors such as psychological, psychosocial, and physical stress [4]. The relationship to AD is further supported by several studies, which show that the CUMS procedure worsens disease progression in genetic AD mouse models [9,10,11]

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