- Mitochondrial Proliferation Gene Promotes Dendritic Growth
- Estrogens and Brain Energy
- Reactivating Memory-Related Genes
- Blocking Glial Cell Activation
- Beta-Amyloid and Sleep-Wake Patterns
- The Brain Resists Toxic Effects of Amyloid
- Disease-Specific Brain Degeneration Patterns
Scientists believe that the abnormal accumulation of beta-amyloid, tau, and other toxic proteins in the brain plays a key role in the loss of communication between neurons and the eventual damage and death of once-healthy brain cells. Beyond these obvious hallmarks of Alzheimer’s disease, researchers are examining a wide range of brain functions and factors that may also play a role in this complex disorder. Research conducted in 2012 and 2013 offered new insights into the cellular and molecular changes that occur in Alzheimer’s disease. Understanding these underlying mechanisms and disease pathways—and how they interact with one another in disease onset and progression—may lead to valid targets for interventions.
A fluorescence image of a neuron in the hippocampus, a region of the brain that plays a critical role in long-term memory. Image courtesy of Rush Medical College.
A study by intramural researchers at the National Institute on Aging suggests that the protein PGC-1α plays an important role in forming and maintaining healthy dendrites and synapses in the hippocampus, a brain region important to learning and memory (Cheng et al., 2012). PGC-1α (proliferator-activated receptor co-activator 1α) acts by stimulating the proliferation of mitochondria. Mitochondria, the “powerhouses” of the cell, generate energy needed for neuronal cell growth and synaptic function. In cultured rat hippocampal neurons, increasing PGC-1α levels resulted in increased numbers of both mitochondria and dendritic spines, whereas knocking out the protein had the opposite effect.
The investigators also found that brain-derived neurotrophic factor (BDNF), a neuronal growth factor involved in learning and memory, stimulated PGC-1α production and mitochondrial proliferation in hippocampal neurons. BDNF is believed to play a key role in the beneficial effects of exercise and cognitive stimulation on brain health, and this study suggests that those beneficial effects may involve BDNF stimulation of PGC-1α levels. Further study is needed to evaluate PGC-1α as a possible therapeutic target for Alzheimer’s disease and other neurodegenerative disorders.
Mitochondria give cells the energy needed to function and survive, and ready reserves of this energy are important to brain health. University of Southern California, Los Angeles, researchers found that treatment with the hormone estrogen boosts mitochondrial function in the brains of female rats that exhibit certain features of human menopause after removal of their ovaries (Irwin et al., 2012).
The researchers treated the rats with synthetic estrogens that selectively stimulate two kinds of estrogen receptors, and found the treatments activated different components of the mitochondrial energy-producing machinery. Because mitochondrial function is impaired in people with Alzheimer’s, the use of synthetic estrogens targeting mitochondrial function could be examined for possible therapeutic benefit.
Memory formation requires changes in gene expression, the switching on or off of specific groups of genes. One mechanism for switching off gene expression involves enzymes called histone deacetylases. Researchers at Harvard University, Cambridge, MA, found that one of these enzymes, histone deacetylase 2 (HDAC2), is activated in the brains of both mouse models of neurodegenerative disease and people with Alzheimer’s, and that the enzyme silences the expression of a variety of genes involved in memory (Gräff et al., 2012).
Using a genetic technique to knock out HDAC2’s function in the hippocampus of the mice, the researchers were able to restore both the expression of memory-related genes and memory function. These findings suggest that cognitive capacities are not entirely lost in neurodegenerative diseases and might be restored by drugs targeting HDAC2.
Glial cells perform many important protective functions for the brain, including mounting defenses against infectious agents and other toxic proteins. Two kinds of glial cells are involved in these defensive responses: astrocytes (named for their star-like shapes) and microglia (named for their diminutive sizes). When faced with potentially toxic proteins, astrocytes and microglia become “activated”: they proliferate and secrete proteins that promote inflammation (cytokines). Normally, these responses help the brain. However, if astrocytes and microglia are chronically activated, as many scientists believe they are in Alzheimer’s, their responses may do more harm than good to the brain.
NIA researchers research the molecular and cellular changes taking place in brains that may lead to Alzheimer’s disease and other dementias.
To learn more about the consequences of astrocyte activation in the Alzheimer’s brain, University of Kentucky, Lexington, researchers injected a protein called VIVIT into the brains of Alzheimer’s model mice (Furman et al., 2012). VIVIT blocks the activation of astrocytes after toxic insults to the brain. After several months of VIVIT therapy, the Alzheimer’s model mice showed reduced astrocyte activation, lower beta-amyloid levels, and improved synaptic and cognitive function. This study suggests that long-term activation of astrocytes has negative consequences for the brain in Alzheimer’s disease, and raises the possibility of developing new therapies targeting astrocyte activation.
Another team of University of Kentucky, Lexington, scientists treated Alzheimer’s disease model mice with a drug, MW-151, previously shown to block glia production of proinflammatory cytokines (Bachstetter et al., 2012). By 1 year of age, untreated Alzheimer’s disease model mice, compared to wild type (control) mice, had higher levels of these cytokines in their brains.
Treating the Alzheimer’s model mice with MW-151 blocked the proliferation of astrocyte and microglia in their brains and blocked brain cytokine production. At the same time, the drug prevented the synaptic degeneration typically seen in this mouse model. The beneficial effects of MW-151 treatment were not accompanied by detectable changes in brain beta-amyloid levels, suggesting the drug may act by blocking glial inflammatory responses to beta-amyloid. Importantly, the drug was more effective when given early in the course of disease progression.
People with Alzheimer’s disease often experience disrupted sleep-wake patterns and may become confused and agitated late in the day and at night. A study at Washington University, St. Louis, suggests that beta-amyloid deposits may contribute to sleep-wake cycle disturbances in people with Alzheimer’s (Roh et al., 2012). In cognitively normal humans and mice, the level of soluble beta-amyloid in cerebrospinal fluid increases during the day and decreases during the night.
The researchers found that the daily rhythm of beta-amyloid in cerebrospinal fluid was disrupted in Alzheimer’s model mice and in people with genetic mutations that cause Alzheimer’s. In the mice, the deterioration of this rhythm coincided with the appearance of beta-amyloid plaques in the brain and the onset of sleep disturbances. Moreover, immunizing the mice with beta-amyloid (a treatment that prevents plaque formation in mice, although not in humans) also preserved their normal sleep patterns. This study suggests that disruptions in sleep-wake patterns could help identify people at risk for developing Alzheimer’s.
Some older people with significant levels of brain beta-amyloid show no obvious signs of cognitive impairment. To better understand this, University of California, Berkeley, researchers performed functional magnetic resonance imaging scans on 45 cognitively normal older adults, age 58 to 97, while the volunteers performed a memory task (Mormino et al., 2012). People with higher levels of amyloid deposits had increased activity in brain areas involved in memory storage and retrieval.
This study suggests that the brains of some older people can compensate for the toxic effects of beta-amyloid by increasing the activation of neural circuits required for memory tasks, thereby delaying the onset of cognitive decline.
Neurodegenerative diseases, including Alzheimer’s disease, affect specific networks of interconnected neurons. Signs of damaged and dying neurons typically appear first in one or two brain regions and then may spread to other regions connected by synapses. Researchers at the University of California, San Francisco, used functional magnetic resonance imaging to analyze connectivity patterns of brain regions that are typically affected in five different neurodegenerative diseases, including Alzheimer’s and frontotemporal dementias (Zhou et al., 2012). The 16 volunteers were cognitively normal, age 57 to 70, and “at rest” during the imaging—that is, not assigned any test activities.
Mathematical modeling of these connectivity patterns suggest that neurodegenerative diseases might spread through the brain via abnormally folded, toxic proteins that move across synapses between interconnected neurons. In Alzheimer’s and other neurodegenerative diseases, these patterns often vary slightly from person to person. Brain image analyses like those done in this study may help predict how a disease and its symptoms progress in individuals.