The Mechanistic Links Between Chronic Kidney Disease and Alzheimer's Disease

When reading about potential mechanistic links between chronic kidney disease and Alzheimer's disease, it is worth considering klotho. Increased expression of klotho has been shown to improve kidney function and better resist the decline of kidney function with age. It also improves cognitive function, though there is some debate over how this is happening. Klotho largely acts in the kidney, and its effects on cognitive function may simply be a compelling demonstration of the point that dysfunction of the kidneys is harmful to organs throughout the body, including the brain.

The mediating mechanisms linking kidney to brain may be the harms done to the cardiovascular system with loss of kidney function, as the brain is sensitive to vascular issues: lowered blood supply; pressure damage due to hypertension; loss of capillary density; leakage of the blood-brain barrier that wraps blood vessels passing through the central nervous system; and so forth. In today's open access paper, researchers discuss how exactly kidney disease may increase the risk and severity of Alzheimer's disease, but the details, particularly those relating to the vasculature, are relevant to other neurodegenerative conditions.

Pathogenesis of Chronic Kidney Disease Is Closely Bound up with Alzheimer's Disease, Especially via the Renin-Angiotensin System

Chronic kidney disease (CKD) is a clinical syndrome secondary to the definitive change in function and structure of the kidney, which is characterized by its irreversibility and slow and progressive evolution. Alzheimer's disease (AD) is characterized by the extracellular accumulation of misfolded β-amyloid (Aβ) proteins into senile plaques and the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau. In the aging population, CKD and AD are growing problems. CKD patients are prone to cognitive decline and AD. However, the connection between CKD and AD is still unclear.

The available evidence suggests that CKD and AD are pathologically related through the renin-angiotensin system (RAS), uremic toxins, and erythropoietin (EPO), which contribute to the occurrence and development of CKD and may aggravate the development of AD. In CKD, excess renin is released and increases circulating angiotensin II (Ang II) levels, resulting in AT1R upregulation and enhancing systemic vascular resistance, increasing blood pressure, and promoting sodium reabsorption in the proximal tubule and (through aldosterone) the collecting duct. In AD animal models, the cerebroventricular infusion of Ang II into aged normal rats increased both tau pathology and amyloid precursor protein (APP) levels, leading to an increase in amyloid-β (Aβ) accumulation. It was also shown that Ang (1-7) expression in the brain increased with disease progression and that there was an inverse correlation between Ang (1-7) level and tau hyperphosphorylation.

In AD model mice, Ang II not only impaired blood-brain barrier (BBB) function in the cerebral microcirculation but also induced inflammatory and thrombotic phenotypes. The binding of Ang II with AT1R damaged the BBB, leading to its leakage and the entry of circulating toxins into the brain. Additionally, AT2R and MasR promoted an M2 anti-inflammatory phenotype in microglia, which is a potential mechanism for alleviating neuronal dysfunction and inflammation and ultimately, for reversing cognition impairment. Based on the current evidence, we propose that the combination of Ang II and AT1R causes BBB leakage and activates microglia to secrete inflammatory factors that lead to apoptosis, neuronal injury, and neurodegeneration, resulting in the aggravation of AD; the activation of the AT2R/MasR axis produces the opposite physiological effect.

It remains unclear whether RAS imbalance in CKD is a cause of AD and vice versa. The following open questions warrant investigation in future studies: (1) Do CKD patients with AD have more severe imbalances in the RAS than those without AD? (2) What are the most significantly altered components of the RAS in CKD patients with AD, and are these components mainly proinflammatory (ACE/AT1R) or anti-inflammatory (ACE2/AT2R/MasR)? (3) Can the use of ACEI/ARB drugs prevent or delay the occurrence of AD? Answering these questions may provide insights that can guide the development of novel treatments for both diseases.

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