Neurology Central

Potential benefits of Angiotensin II receptor blockade for the treatment of preclinical, early Alzheimer’s disease

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We have recently published [1] evidence demonstrating that candesartan, an Angiotensin II AT1 receptor blocker (ARB), is a promising candidate therapeutic for early Alzheimer’s disease. The present report elaborates on this publication and helps to place the recent results in an appropriate context.

Background

Alzheimer’s disease is the most frequent age-related dementia, a progressing, devastating illness currently without effective treatment. Although its incidence advances with age, several gene mutations and medical risk factors injuring the brain increase individual vulnerability to the disease several-fold. They include, but are not limited to cardiovascular disease, in particular hypertension, metabolic disorders such as diabetes, chronic kidney disease and traumatic brain injury.

While alterations in amyloid metabolism are considered the hallmark of Alzheimer’s disease, progression of the illness starts many years before, with microvascular and metabolic alterations as primary early injury factors [2, 3].

A working hypothesis substantiated by experimental and clinical evidence suggests that chronic ischemia leads to metabolic alterations, progressive cell loss and decreased brain function [2]. By the time Alzheimer’s disease is clinically diagnosed, many years later, major and irreversible cell injury has already occurred. This explains therapeutic failures initiated late in the progression of the illness, and makes it imperative to identify agents effective against early, presymptomatic injury mechanisms and risk factors [3].

A class of compounds blocking receptors for Angiotensin II, the angiotensin receptor blockers (ARBs), may offer significant therapeutic benefits for presymptomatic, early Alzheimer’s disease [3, 4]. Angiotensin II regulates cardiovascular, metabolic and brain function. However, overactivity of its physiologically active AT1 receptors is associated with disease. Higher AT1 receptor activation leads to alterations in cardiovascular, metabolic and kidney function affecting the brain, and is associated with direct brain injury, resulting in progressive loss of function [5, 6].

It may be concluded that the blockade of excessive Angiotensin II AT1 receptor activation may have potential and multiple therapeutic benefits. This hypothesis has been conclusively demonstrated, and ARBs, compounds with excellent safety records, are now commonly used for the treatment of cardiovascular disease, including hypertension, metabolic alterations and chronic kidney disease, the major clinical risk factors for Alzheimer’s disease [3].

Surprisingly, until recently ARBs have not been considered for the treatment of brain disorders, with the exception of stroke. However, it is now becoming clear that treatment with ARBs has the potential to significantly alter the therapeutic approach to neurodegenerative brain disease.

Accumulating evidence indicates that in addition to their cardiovascular benefits, ARBs are strongly neuroprotective. Experiments in cultured brain cells demonstrate ARB neuroprotection against several mechanisms of injury prevalent in early Alzheimer’s disease: inflammatory factors such as the proinflammatory cytokine, termed interleukin-1β and the bacterial endotoxin lipopolysaccharide, excessive, neurotoxic glutamate concentrations [7], and oxygen and glucose deprivation, representative of hypoxia and metabolic deficit. ARB administration was also effective in several mouse models of Alzheimer’s disease, restoring cognition and motor function [3]. In addition, retrospective analysis indicates that when hypertension was treated with ARBs in comparison with other equally effective antihypertensive compounds, the development of Alzheimer’s disease was significantly delayed [8]. Furthermore, numerous controlled, statistical and observational studies indicate that treatment with ARBs protects cognition when impaired by cardiovascular and metabolic disorders, in particular hypertension [3, 5].

The conclusion of this work was therefore that ARB treatment could be of therapeutic benefit for medical risk factors for Alzheimer’s disease, protecting cognition, and that these compounds may be excellent neuroprotective agents.

The stage was therefore set for an in-depth study aiming to demonstrate whether or not there was a correlation between results obtained in the laboratory with alterations demonstrated in autopsy samples obtained from the brains of patients diagnosed with Alzheimer’s disease.

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