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.

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“…Some clinical and meta-analysis studies have also shown that ACEIs reduce the progression and risk of AD [ 184 , 185 , 186 , 187 ]. This result has also been observed in several animal model studies [ 188 , 189 , 190 ]. However, in one meta-analysis study, ACEIs had no effect on cognitive decline [ 191 ], and some studies have shown a negative effect of ACEIs in in-vivo AD models [ 192 , 193 , 194 ].…”

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“…Some ACEIs even reduced Aβ peptide level in animal models of AD ( AbdAlla et al, 2013 ). Moreover, ACEIs showed beneficial effect in reducing AD signs and symptoms ( Dong et al, 2011 ; Tota et al, 2012 ; AbdAlla et al, 2015 ). Administration of perindopril (ACEI) has shown an instrumental effect in increasing density of normal neurons and improving learning and memory ( Hou et al, 2008 ).…”

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“…This catabolism is mainly mediated through IRAP activation (vasopressin, oxytocin, somatostatin and cholecystokinin) , but ACE contributes to the catabolism of other metabolites, such as substance P, neurotensin, dynorphin and encephalin . ACE participates in neurodegeneration induced by environmental stress, a major factor of AD pathology. Glutamate neurotoxicity and neurodegeneration are increased by genes which downregulate microtubule‐associated protein 2 ( Map2 ), synuclein‐gamma ( Sncg ) and glutamate decarboxylase 2 ( Gad2 ) . This downregulation occurs through angiotensin 1 receptor (AT1R) activation.…”

“…This downregulation occurs through angiotensin 1 receptor (AT1R) activation. In a rat model of chronic unpredictable stress, ACE hippocampal upregulation and tau hyperphosphorylation could be averted by treatment with central‐acting captopril . AT1 receptors in brain vessels control cerebrovascular flow and vessel autoregulation and thus contribute to regulate oxygen and nutrient supply to the brain . Overactivation of AT1 receptors in neurons blocks hippocampal long‐term potentiation , increases oxidative stress and promotes neuroinflammation .…”