Evidence for APOEε4 to Speed Neurodegeneration by Altering Macrophage Function – Fight Aging!
The primary function of the APOE protein is lipid transport, appearing in many of the different forms of cholesterol transport particles. Like all proteins in the body APOE is involved in more processes than just its primary function. There are a number of common variants of the APOE gene, all slightly altering the behavior of the protein. The APOEε4 variant is notable because it significantly increases the risk of suffering Alzheimer’s disease; in other words it accelerates age-related neurodegeneration.
In recent years, evidence has pointed to the effects of APOEε4 on the innate immune cells known as microglia, found in the brain but not the rest of the body. APOEε4 makes microglia more inflammatory, and increased microglial inflammation is strongly implicated in brain aging. Microglia are the central nervous system version of the innate immune cells called macrophages found everywhere else in the body. Macrophages in tissues very close to the brain, such as the choroid plexus, are known as border-associated macrophages and their inflammatory behavior is also implicated in the progression of neurodegenerative conditions.
Interestingly, the authors of today’s open access paper report that APOEε4 is disruptive to the behavior of border-associated macrophages. They focus on the generation of oxidative stress by macrophages rather than inflammation, but it is worth noting that inflammation and oxidative stress usually go hand in hand in aged tissues.
Microvascular damage to the subcortical white matter is a major contributor to age-related dementia, including Alzheimer’s disease (AD). Supplied by terminal arterioles with limited collateral flow from adjacent vascular territories, the subcortical white matter is particularly vulnerable to microvascular injury. Although vascular risk factors, such as hypertension and diabetes, are strongly linked to white matter lesions, accumulating evidence indicates that ApoE4, the leading genetic risk factor in sporadic AD, also increases the risk for cognitive impairment produced by vascular factors. Thus, ApoE4 carriers exhibit vascular pathology, microvascular alterations, and more white matter lesions linked to cognitive impairment.
ApoE4 is well known to be associated with alterations of the neurovasculature. ApoE4-positive individuals have dysregulated cerebral blood flow (CBF), as well as increased permeability of the blood-brain barrier (BBB) in the setting of AD. However, the cellular sources of ApoE4, the effector cells in the cerebral microvasculature and the signaling mechanisms driving the dysfunction remain unclear.
Although microglial cells reside in the brain parenchyma, border-associated macrophages (BAMs) seed the meninges, the choroid plexus and the space surrounding microvessels as they dive into the brain (perivascular space). BAMs are enriched with free radical-producing enzymes and, owing to their proximity to pial arterioles in the leptomeninges and to penetrating arterioles in the perivascular space, have recently emerged as a major cause of neurovascular dysfunction in animal models of neurodegeneration.
In the present study, we investigated the sources and targets of ApoE responsible for neurovascular dysfunction and the mechanisms of the effect. We found that ApoE4 acts on BAMs to alter critical cerebrovascular regulatory mechanisms through NADPH oxidase (NOX)-dependent production of reactive oxygen species (ROS). The dysfunction is abolished by BAM depletion or by genetic deletion of ApoE4 selectively in BAMs, identifying these cells as the sole source of the ApoE4 mediating the deleterious vascular effects.
Using a bone marrow (BM) transplantation strategy, we found that ApoE4-positive BAMs induce neurovascular dysfunction in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue neurovascular dysfunction in ApoE4-TR mice, indicating that BAMs are also the main effectors of the dysfunction. Attesting to the pathogenic effect of BAM ApoE4 on white matter injury, ApoE4-positive BAMs enhance white matter damage and cognitive impairment in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue this phenotype in ApoE4-TR mice. The findings establish BAMs as both sources and effectors of the ApoE4 acting on the cerebral microvasculature, unveiling a previously unappreciated cell-autonomous role of brain-resident macrophages in the neurovascular dysfunction and propensity of white matter injury associated with ApoE4.
