Research in 2011 and 2012 offered new insights into how Alzheimer’s disease impacts not only neurons, but also brain inflammatory responses, glial cell biology, and vascular function. In addition, because age is the major risk factor for Alzheimer’s, increasing attention has turned to the normal, age-related changes in cellular and brain networks.
Recent neuroimaging studies have shown that 25- to 50-percent of cognitively normal older adults have significant accumulations of brain beta-amyloid, which may represent an early stage of the Alzheimer’s disease process. In a post mortem study led by University of Washington, Seattle, researchers, the brains of many cognitively normal older adults showed signs of other dementia disorders as well (Sonnen et al., 2011).
The researchers obtained post mortem brain samples from more than 300 volunteers who lived on average between 80 and 90 years. They analyzed the tissue under the microscope for signs of three common dementias: Alzheimer’s, Lewy body disease, and vascular brain injury from stroke or other vascular disease. Alzheimer’s disease was the most common pathology, found in 47 percent of the brains. Vascular brain injury occurred in more than one-third of the volunteers, while 15 percent showed signs of Lewy body disease.
These findings indicate that the brains of a large proportion of cognitively normal older people show accumulations of cellular damage, likely the result of one or more diseases or other factors influencing brain health over the lifespan. Studies like these intensify our interest in how people with such damage in their brains can still enjoy normal cognitive function.
Neurofibrillary tangles are a hallmark of Alzheimer’s disease. Tangles are composed of misfolded forms of the protein tau—a structural change that results in tau clumping into insoluble fibrils that, under the microscope, resemble threadlike fibers. What causes tau to misfold and lose function has long been a mystery.
A University of Pennsylvania, Philadelphia, study using kidney cells suggests a “domino effect” in which misfolded tau causes normal tau to misfold (Guo and Lee, 2011). The researchers found that minute quantities of misfolded tau introduced into cultured cells expressing normal tau caused the tau to form fibrils like those seen in the Alzheimer’s brain. In addition, the researchers found that the cells soaked up the misfolded tau from the fluid surrounding them. Assuming that brain cells also take up tau, this study suggests a route by which tau pathology could spread from one neuron to another, as it appears to do in Alzheimer’s disease.
As Alzheimer’s disease progresses, tau pathology spreads from one brain region to another in a consistent pattern Tangles appear first in the entorhinal cortex, next in the hippocampus, and then in the cerebral cortex. These brain regions are connected to one another via synapses that create communication networks.
Research groups at Columbia University, New York City, and Harvard University, Cambridge, MA, have now shown that abnormal tau spreads from one brain region to the next by moving across synapses (Liu et al., 2012; de Calignon et al., 2012). Each research group performed similar experiments in which they created experimental mice that expressed mutant human tau only in the entorhinal cortex. As the mice aged, the mutant tau gradually spread across the connected brain regions. As the abnormal human tau appeared in each brain region, it clumped together with normal mouse tau to form tangles and damage synapses.
These studies demonstrate one mechanism by which Alzheimer’s pathology can spread from one brain region to another. They also suggest a possible target for therapies that might delay or prevent disease onset and progression.
Mitochondria are the “powerhouses” of the cell, generating the energy needed to function and survive. In Alzheimer’s disease, abnormal levels of beta-amyloid damage brain mitochondria, leading to neuronal dysfunction. A team led by investigators at Columbia University, New York City, found that beta-amyloid interacts with mitochondria by binding to a mitochondrial enzyme called ABAD (beta-amyloid-binding alcohol dehydrogenase) (Yao et al., 2011). Treating Alzheimer’s model mice with a peptide that blocks beta-amyloid binding to ABAD improved mitochondrial function and also alleviated the mice’s memory deficits. This study strongly implicates mitochondrial beta-amyloid as a critical player in the development of Alzheimer’s disease.
Synapses depend on nearby mitochondria to generate the energy needed for proper functioning. A study led by Harvard University, Cambridge, MA, researchers showed that abnormal forms of tau disrupt this process (Kopeikina et al., 2011). In mice expressing a mutant form of human tau, neurons lacked the mitochondria needed for proper functioning; similar abnormalities were seen at autopsy in people diagnosed with Alzheimer’s. The researchers also found that tau does not have to form thread-like fibrils to disrupt mitochondria from delivering energy to synapses. Rather, reduced levels of normal tau in mouse models are enough to disrupt the process.
Working memory is the ability of the brain to store and manipulate information over brief periods of time. It is critical to tasks of daily living such as planning dinner and keeping the list of ingredients in mind while pulling them out of the refrigerator. Many of the cognitive changes experienced by normal adults (forgetfulness, distractibility, reduced efficiency in carrying out tasks) result from declines in working memory. Research now shows that multitasking impairs working memory performance, especially as we age.
University of California, San Francisco, researchers used functional magnetic resonance imaging scanning to study brain networks in younger and older adults who were asked to perform a working memory task (Clapp et al., 2011). The researchers then intentionally distracted the participants during the task. Both younger and older adults redirected their brain networks from the assigned task to the interruption. However, unlike younger adults, older adults failed to disengage their attention from the interruption and failed to reestablish functional connections with the memory network originally engaged in the task. The inability to disengage from distraction is likely to impact a wide range of life activities, particularly in the information age, which requires increasing organizational skill to deal with even basic needs such as medical care and paying bills.
These images of the hemispheres of the brain show that Alzheimer’s disease appears to damage the left side of the brain more than the right side. In fact, this composite image of the brains of older people shows about a 15 percent loss of volume in the left hemisphere of the brain. Significantly, this area plays a critical role in language, and people with Alzheimer’s often experience significant declines in their ability to use and process language.
Courtesy of Paul M. Thompson, PhD, and Arthur W. Toga, PhD, Laboratory of Neuro Imaging, UCLA.
To understand the cellular changes underlying age-related decline in working memory, researchers from Yale University, New Haven, CT, studied rhesus monkeys. Like humans, they may develop problems with working memory in their senior years (Wang et al., 2011). The researchers showed that this loss is tied to changes in a specific network of neurons in the prefrontal cortex, the brain region responsible for working memory. In younger animals, these prefontal cortex neurons continue to fire in response to an environmental signal after the signal is removed. However, with age, the researchers found, the firing rates of these neurons declined steeply.
Taking the experiment a step further, they found that the decline could be reversed in the monkeys by directly delivering drugs to the brain that inhibit cyclic AMP, an intracellular signaling molecule. The beneficial response suggests that declines in age-related working memory may be reversible. One of the cyclic AMP inhibitors used in this study, guanafacine, is already approved by the U.S. Food and Drug Administration to treat high blood pressure. A pilot clinical trial is now underway to see if this medication can improve working memory in cognitively normal older people.
Brain neurons have a remarkable capacity to remodel their connections with other neurons in response to changes in the environment. This phenomenon, known as “synaptic plasticity,” is critical for memory processes and for behavioral adaptation to changes in the environment. However, Mt. Sinai Medical Center, New York City, researchers found that in rats, the remodeling capacity of neurons diminishes with age in the prefrontal cortex, a brain region involved in learning and memory (Bloss et al., 2011).
When young rats experienced 3 weeks of behavioral stress, neurons in their prefrontal cortex responded by retracting and/or reshaping their dendritic spines. In contrast, the dendritic spines of middle-aged and aged rats did not remodel during stress. Since the prefrontal cortex plays a central role in working memory, loss of synaptic plasticity in this brain region may contribute to age-related loss of working memory function.
Neurons do not function in isolation, but in close collaboration with blood vessels and glial cells, which support and protect brain cells. Like neurons, glial cells and blood vessels show changes in structure and function in both Alzheimer’s disease and normal aging. These changes can impair healthy brain function.
Astrocytes, a type of glial cell, are star-shaped cells that surround and help regulate, support, and protect neurons and blood vessels. One of many critical functions astrocytes perform is to secrete growth factors that stimulate neurogenesis, or the birth of new neurons. Recognizing that neurogenesis declines as the brain ages, researchers at Rosalind Franklin University, Chicago, studied how aging impacts astrocytes (Bernal and Peterson, 2011).
They found that astrocytes in the brains of aging rats showed signs of structural changes similar to those seen during mild brain inflammation and decreased levels of neuronal growth factors. Importantly, the brain regions in which these astrocyte changes were seen included parts of the hippocampus, where new neurons are generated. These findings indicate that decreased availability of astrocyte-derived growth factors may contribute to age-related declines in neurogenesis.
Another important function astrocytes perform is to protect neurons against damage by free radicals. Free radicals are highly reactive molecules that can build up inside cells due to aging or other factors and cause cellular damage, a condition known as “oxidative stress.” Astrocytes protect neurons from oxidative stress by generating antioxidants, molecules that neutralize free radicals and render them harmless.
University of Michigan, Ann Arbor, researchers exposed cultured mouse astrocytes to beta-amyloid, which causes oxidative stress in neurons (Garg et al., 2011). Beta-amyloid disrupted astrocyte antioxidant production pathways and simultaneously interfered with the astrocytes’ ability to protect neurons against beta-amyloid toxicity. These results suggest the possibility of developing Alzheimer’s disease therapeutics by enhancing astrocyte antioxidant production pathways.
Researchers are interested in finding out how physical exercise may influence cognitive health into late age. University of Kentucky, Lexington, researchers showed that exercise benefits aging glial cells (which support and protect neurons), blood vessel cells, and neurons (Latimer et al., 2011). The researchers compared the brains of middle-aged female mice with and without access to exercise wheels. (Mice provided with exercise wheels tend to run on them without encouragement.) After only 6 weeks, the exercising mice showed significant reductions in markers of glial and blood vessel cell aging compared with the sedentary mice.
The Alzheimer’s disease brain shows signs of ongoing inflammation, a tissue response to cellular damage. In the short-term, inflammation helps neutralize and flush out harmful substances. However, the inflammatory response may damage tissue if it goes on for too long. A University of California, Irvine, study suggests that chronic inflammation contributes to neurodegeneration in Alzheimer’s disease (Kitazawa et al., 2011).
The researchers treated Alzheimer’s model mice with an antibody that blocks Interleukin 1, a molecule that promotes inflammation and is abnormally elevated in people with Alzheimer’s. Blocking this molecule not only reduced inflammation, but also decreased tau and beta-amyloid levels and improved cognition in the mice. These findings indicate this molecule may be a target for developing interventions to treat Alzheimer’s disease.
A University of Rochester, NY, study suggests that the APOE gene increases Alzheimer’s disease risk by setting off an inflammatory response that leads to breakdown of the blood-brain barrier, a specialized filter that allows blood-vessel cells in the brain to prevent harmful substances in blood from entering the brain (Bell et al., 2012). In transgenic mice that either lacked the apolipoprotein E (APOE) gene or had the APOE ɛ4 allele (the allele that increases Alzheimer’s risk), the blood-brain barrier breaks down, brain blood vessels begin to leak, toxic proteins enter the brain, and neurons degenerate.
The researchers found that the critical factor causing blood-brain barrier breakdown in the transgenic mice was an inflammatory protein called cyclophilin A (CypA). Both APOE ɛ2 and APOE ɛ3 genes can keep CypA production in check, but mice with the APOE ɛ4 gene lacked this ability. However, inhibition of the CypA pathway partially reversed neurodegeneration in the transgenic mice, suggesting this pathway as a therapeutic target. Importantly, no beta-amyloid accumulation was seen in the transgenic mice, which suggests that inflammation and blood-barrier breakdown may precede beta-amyloid accumulation in the Alzheimer’s disease process.
One function of microglia cells is to clear away cellular debris. Microglia cluster around beta-amyloid plaques but do not digest them efficiently unless they are “activated” by signaling molecules that promote brain inflammation. Researchers at Cornell Medical College, New York City, studying microglia in mouse tissue asked how activation enables microglia to digest beta-amyloid. They found that unactivated microglia can engulf beta-amyloid fibrils and deliver them to lysosomes, the cellular organelles responsible for protein digestion (Majumdar et al., 2011). However, these lysosomes are not acidic enough to allow digestion unless they are exposed to a proinflammatory signaling molecule. This finding suggests that agents that regulate the acidity of microglial lysosomes may offer a potential therapeutic approach for Alzheimer’s disease.
In a set of transfusion experiments that involved old and young mice, researchers from Stanford University, Palo Alto, CA, showed that factors in the blood of young mice can rejuvenate the brains of old mice (Villeda et al., 2011). The old mice subsequently showed more youthful levels of neurogenesis (birth of new neurons) in the hippocampus, a region of the brain important to learning and memory. In contrast, the young mice showed reduced neurogenesis and developed learning and memory deficits. The researchers identified a factor in the blood of old mice that was responsible for squelching neurogenesis in the young mice: the immune system protein eotaxin, which plays a role in allergic responses. This study shows that age-associated declines in neurogenesis may be reversible.
Much of our current understanding of Alzheimer’s disease biology comes from studies in mouse models. However, monitoring disease development in mice typically requires time-consuming behavioral tests and/or post mortem analyses of brain tissue. University of California, San Francisco, researchers used a new method called “bioluminescence imaging” to rapidly and noninvasively monitor disease progression in the living brains of Alzheimer’s model mice (Watts et al., 2010). The new imaging tool tracks disease-related changes in brain astrocytes, the star-shaped cells that help support brain health. Astrocytes increase in number and express more of a gene called glial fibrillary acidic protein (GFAP) in Alzheimer’s disease.
To study this process, the researchers created a line of Alzheimer’s model mice in which part of the GFAP gene was attached to a fluorescent “reporter” gene, a gene that produces a fluorescent protein. They monitored GFAP levels by fluorescence imaging. As the mice aged, their brain astrocytes accumulated fluorescent protein that correlated closely with that of brain beta-amyloid plaque accumulation. The use of this technique should facilitate the testing of Alzheimer’s therapeutics in mouse models.
The use of animal models for Alzheimer’s disease research has been useful but difficult, in part because mouse cells do not behave like human cells. For example, unlike humans, mice modeled to develop amyloid plaques do not exhibit tau tangles, a hallmark of human disease. Promising studies, however, have developed new human cellular models for studying Alzheimer’s biology.
Through the use of genetic engineering techniques, University of California, San Diego, researchers created neurons from cultured skin cells of people with familial Alzheimer’s disease (Israel et al., 2012). Compared to neurons made from skin cells of cognitively normal volunteers, neurons made from Alzheimer’s volunteers showed Alzheimer’s-like features, including high levels of abnormal tau as well as beta-amyloid. In addition to development of this important model, the researchers found evidence that both tau and amyloid pathology may result from abnormal processing of amyloid precursor protein (APP) but develop along different pathways. This finding is of considerable clinical significance, as it suggests that drugs targeting beta-amyloid may not improve tau pathology.