Targeting the neuronal renin-angiotensin system in prevention of neurodegeneration and dementia

抄録

The involvement of the renin-angiotensin system in the pathogenesis of cardiovascular diseases is well-established. In contrast, the contribution of this system to prevailing neurodegenerative diseases and dementias such as Alzheimer`s disease is still under investigation. In frame of our research we investigated the impact of angiotensin-converting enzyme (ACE) inhibition in the APPSwe Tg2576 model of familial Alzheimer`s disease (AD). We found that major histopathological features of AD such as hippocampal Amyloid-beta (Abeta) plaque formation were retarded by 6 months of treatment with the brain-penetrating ACE inhibitor, captopril. Whole genome microarray gene expression profiling, immunoblotting and immunohistology demonstrated up-regulation of the ACE protein in hippocampal neurons of aged AD mice, which was prevented by ACE inhibition. In addition, captopril promoted the induction of a neuro-regenerative gene expression profile in AD mice. The ACE protein was localized in hippocampal vessels and neurons in close proximity to Abeta plaques and the angiotensin II AT1 receptor. In search for the trigger of ACE up-regulation, we used the chronic unpredictable mild stress model (CUMS), which mimics major features of sporadic AD. We found that four weeks of chronic mild stress induced a 2-fold up-regulation of hippocampal ACE. Treatment with captopril during the stress protocol significantly retarded early hippocampal AD markers such as tau hyperphosphorylation and Abeta accumulation. The decreased neurodegenerative process was accompanied by the preservation of major neuronal structure proteins such as synuclein-gamma. ACE inhibition could also neutralize glutamate excitotoxicity by preventing the stress-induced loss of glutamic acid decarboxylase. Taken together, up-regulation of hippocampal ACE is a common feature in familial and sporadic AD models, and treatment with a brain-penetrating ACE inhibitor retards major neuropathological hallmarks of AD, largely by inhibition of ACE-mediated release of angiotensin II and subsequent dampening of AT1 receptor stimulation. In view of the neuro-regenerative potential of ACE-AT1 receptor inhibition, we currently aim to identify neuro-protective targets within the ACE-angiotensin system, which could be further exploited to develop urgently needed pharmacological treatment approaches for AD and neurodegeneration.