Cholesterol’s Function and Origin in the Alzheimer’s Disease Brain

Alzheimer’s disease (AD) has been associated with altered lipids in the brain since its first description over 100 years ago [1]. Some direct measurement of cholesterol show’s increased levels with disease severity and age [2, 3] but not all [4]. Despite its well-known role in the periphery, cholesterol’s neuroinflammatory role in AD has remained largely tangential to other proposed mechanisms. This is partly due to a lack of understanding brain cholesterol, its pools that signal inflammation in the brain, its variability, and the belief that most brain cholesterol is produced locally, separated from circulating blood cholesterol by the blood-brain barrier (BBB). However, in the disease state, the barrier breaks down, allowing cholesterol-containing lipoproteins and even whole immune cells from the periphery to enter the brain. This raises the question, what does peripheral cholesterol do to the brain?

A new theory, articulated by Jonathan Rudge, suggests that the entrance of peripheral cholesterol is a causal event critical for the onset of AD [5]. The evidence presented for cholesterol is strong. A pool of elevated cholesterol from astrocytes regulates the production of amyloid proteins and tau phosphorylation [6], removal of a cholesterol transport protein (apolipoprotein E (apoE)) to immune cells reduces tau and neuroinflammation [7], and the naturally occurring apoE isotype 4 (apoE4) is the number one genetic marker for late-onset AD [8].

Over the last several decades research has shown the BBB can temporarily become permeable, including to immune cells from the blood [9]. And for this reason, the concept that the brain is an isolated immuno-privileged tissue may be challenged. Based on the important role of cholesterol in peripheral inflammation [10], we expect the permeation of circulating lipids/cholesterol to be a potent driver of inflammation in the brain.

Nonetheless, major questions remain. The brain has its own pools of cholesterol and its own innate immune cells that respond independently of circulating cholesterol. How does brain derived cholesterol contribute to AD? Can brain cholesterol spiral out of control, or does it merely open the BBB and enable peripheral lipids their ultimate causative effect? Are the mechanisms of late-onset and early-onset diseases equally affected by the proposed invading cholesterol? Huntington’s disease and Parkinson’s disease generate protein aggregates [11] that presumably induce inflammation prior to the BBB opening; how does invading cholesterol affect these models? And does metabolism of cholesterol and amyloid in the periphery affect AD directly [12, 13]?

Lastly, if invading cholesterol causes a major disease phenotype, then sealing off the cholesterol from circulation must be part of a biological process necessary for healing and homeostasis. This perspective can generate new testable hypothesis. For example, an early description of AD suggested amyloid plaques may serve as a “scab” [14]. Interestingly, removal of amyloid plaques by immunotherapy causes microhemorrhage in the AD brain [15]. If the plaques evolved to stop the invasion of cholesterol/lipid across the BBB or the parenchyma, then removing plaques should cause microhemorrhage and edema. As we consider the lipid invasion model and design novel experiments, the data will shed new light on the age-old problem of neurodegeneration.