Connecting the brain cholesterol and renin-angiotensin systems: potential role of statins and RAS-modifying medications in dementia.

Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications.

Targeting Alzheimer's disease with gene and cell therapies.

Alzheimer's disease (AD) causes dementia in both young and old people affecting more than 40 million people worldwide. The two neuropathological hallmarks of the disease, amyloid beta (Aß) plaques and neurofibrillary tangles consisting of protein tau are considered the major contributors to the disease. However, a more complete picture reveals significant neurodegeneration and decreased cell survival, neuroinflammation, changes in protein and energy homeostasis and alterations in lipid and cholesterol metabolism. In addition, gene and cell therapies for severe neurodegenerative disorders have recently improved technically in terms of safety and efficiency and have translated to the clinic showing encouraging results. Here, we review broadly current data within the field for potential targets that could modify AD through gene and cell therapy strategies. We envision that not only Aß will be targeted in a disease-modifying treatment strategy but rather that a combination of treatments, possibly at different intervention times may prove beneficial in curing this devastating disease. These include decreased tau pathology, neuronal growth factors to support neurons and modulation of neuroinflammation for an appropriate immune response. Furthermore, cell based therapies may represent potential strategies in the future.