Cellular Changes in Alzheimer’s Disease

Calcium Imbalance in Neurons

Scientists have known since 1995 that two gene mutations—presenilin-1 and presenilin-2—cause early-onset Alzheimer’s disease, but exactly how is unclear. Because abnormal presenilin proteins are involved in a cascade of events that eventually results in amyloid plaques, previous research has focused on that aspect of presenilin function. However, presenilin mutations also disturb the calcium balance in neurons. Researchers at the University of Texas Southwestern Medical Center, Dallas, have now linked this phenomenon to the development of Alzheimer’s-like pathology in mice (Zhang, Sun, et al., 2010).

outline of a neuronThe researchers studied cultured hippocampal and other brain cells from mouse models with a mutant form of the human presenilin gene. Disabling the presenilin function caused calcium to build up inside the hippocampal cells and prevented the slow release of calcium that is necessary for the health of the cell. In further testing, the researchers blocked other channels the cells might use to release calcium so that the cells could not find other ways to compensate for presenilin dysfunction. This made the Alzheimer’s-like pathology even worse. These results unveil a new mechanism explaining how presenilin mutations might lead to the disease. They also suggest that calcium imbalance in neurons may fuel beta-amyloid accumulation and the onset of Alzheimer’s.

Additional references:

  • Gleichmann M et al. (2012). Molecular changes in brain aging and Alzheimer’s disease are mirrored in experimentally silenced cortical neuron networks. Supported by NIA.
  • Yang L et al. (2009). Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. Baylor College of Medicine. Supported by NIA.

How Tau Tangles with Neurons

Tangles and other abnormal forms of tau protein accumulate inside the brain cells of people  with Alzheimer’s. Together with beta-amyloid, they contribute to neurodegeneration. Tangles were long considered the toxic form of tau protein, but increasing evidence points to abnormal forms of soluble tau as more likely suspects. In healthy neurons, soluble tau is concentrated in axons and less abundantly in cell bodies and dendrites. In studying mouse neurons expressing either normal or mutant forms of tau, University of Minnesota, Minneapolis-St. Paul,  researchers found that mutant tau ignores its usual cellular boundaries and strays into dendrites, where it accumulates inside spines and interferes with the ability of synapses to communicate via chemical messengers and receptors (Hoover et al., 2010).

The scientists further discovered that mutant tau’s movement into dendrites results from excessive (hyper) phosphorylation of the protein. Phosphorylation is a process cells often use to regulate a protein’s function or level of activity. Less heavily phosphorylated forms of tau stayed out of dendrites; heavily phosphorylated forms penetrated them more extensively. These findings support other studies pointing to hyperphosphorylated forms of tau as culprits in Alzheimer’s disease, and suggest that their toxic effects result in part from disruption of the brain cell’s ability to signal other neurons.

Normal as well as mutant forms of tau may contribute to neurodegeneration. For example, in Alzheimer’s model mice that accumulate high levels of beta-amyloid, lowering tau levels can reduce damage to brain cells. What role does tau plays in disease progression? A University of California, San Francisco-led study suggests that tau offers beta-amyloid a foothold in the disruption of axonal transport, a process by which neurons move no longer needed fats, proteins, and other cell parts down their axons and away from the cell body. They looked at how the process differed between cultures of brain cells of normal mice and mice whose tau levels had been reduced or removed. They found the transport of certain cell parts were similar in both normal and tau-deficient neurons—at least until beta-amyloid was added to the mix. With beta-amyloid, the percentage of cell parts being transported dropped by almost half in the normal neurons, but was unchanged in the neurons with reduced tau levels. These results indicate tau interacts with beta-amyloid during axonal transport and may play a role in the toxic effects of Alzheimer’s disease (Vossel, 2010).

Additional reference:

  • Luebke JI et al. (2010) Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models. Boston University School of Medicine. Supported by NIA, NIDCD, and NIMH.

Mitochondria and Energy Disruption

Mitochondria are the parts of the cell that use oxygen to produce energy for the cell via a chemical process. The mitochondria are highly mobile; pushed and pulled by proteins, they travel along a network of protein rods that connect various parts of the cell. Disruption of energy production can be disastrous for cells, as activities grind to a halt without the energy supplied by mitochondria.

Abnormal accumulation of beta-amyloid around neurons may impair mitochondria involved in cell-to-cell communications between synapses. Researchers at Columbia University, New York City, studying Alzheimer’s model mice found that beta-amyloid is also deposited inside synaptic mitochondria, and that the deposits increased with age (Du, Guo, et al., 2010). Synaptic mitochondria showed impaired energy production, increased vulnerability to damage by calcium, and earlier signs of distress. The scientists also found that low concentrations of beta-amyloid added to mouse neurons in culture slowed the movement of mitochondria up and down axons and decreased their size. Mitochondrial size was also decreased in neurons treated with beta-amyloid. The findings suggest that synaptic mitochondria appear especially sensitive to injury by beta-amyloid, and their dysfunction may be an early step in the Alzheimer’s disease process.

Injury to synaptic mitochondria caused by beta-amyloid may also negatively impact their ability to respond to neurotransmitters, or chemical messengers, in the brain. An Emory University, Atlanta, study showed that beta-amyloid added to neurons in culture could disrupt the movement of energy-vital mitochondria into dendritic spines, a process necessary to stimulate synapses and communication (Rui et al., 2010). At the same time, a type of neurotransmitter receptor—AMPA, which is important to memory formation—failed to function normally. The scientists examined several hundred individual spines and found that spines lacking mitochondria were the same ones that had lost their supply of AMPA receptors. Treating neurons with a compound known to block beta-amyloid suppression of mitochondrial transport reversed this loss. These findings suggest that synaptic mitochondria may be essential for supporting the ongoing supply of AMPA receptors to synaptic membranes, and that function is disrupted by beta-amyloid.

Sometimes cells release free radicals, a molecule (typically oxygen or nitrogen) that can cause damage. While cells maintain complex systems of antioxidants (molecules that block free radicals), a buildup of free radicals may result in a condition known as “oxidative stress.” A Baylor College of Medicine, Houston, study suggests that mitochondria may be a major source of the free radicals that cause the oxidative stress typically found in Alzheimer’s disease (Massaad et al., 2010). The scientists developed an Alzheimer’s disease mouse model that produces extra high levels of superoxide dismutase-2 (SOD-2), an enzyme that specifically scavenges free radicals produced by mitochondria. Ramping up the levels of this enzyme reversed two Alzheimer’s disease-like factors—impaired blood flow in the brain and impaired communication between axons. This study points to free radicals from mitochondria as a major influence in Alzheimer’s disease, and suggests that antioxidants specifically targeting them might be explored as possible therapeutics.

Nerve cells use glucose as their main energy source; mitochondria are responsible for converting glucose to energy. When mitochondrial function declines, the function of nerve cells declines, and they are forced to shift to less efficient fuel sources. One factor that may aggravate this decline in mitochondrial function and brain metabolism could be the loss of estrogen experienced during menopause, according to a University of Southern California, Los Angeles, study of female mice (Yao et al., 2010).

The researchers found that the brains of postmenopausal but cognitively normal mice indicated a shift from glucose to alternative energy sources, resembling those of premenopausal Alzheimer’s model mice. Meanwhile, the early metabolic changes occurring in Alzheimer’s model mice accelerated even further after menopause. These results expand upon previous evidence that estrogen supports mitochondrial use of glucose as a primary energy source and suggest that loss of this support may underlie the increased risk for Alzheimer’s disease in menopausal women. They are also consistent with new evidence from human studies that there may be a critical “window of opportunity” around the time of menopause when estrogen therapy may be of cognitive benefit. See Hormones and Cognitive Health in Postmenopausal Women.

Additional references:

  • Crews L et al. (2010) Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. University of California, San Diego. Supported by NIA.
  • Du H, Yan SS. (2010) Mitochondrial permeability transition pore in Alzheimer’s disease: cyclophilin D and amyloid beta. Columbia University College of Physicians and Surgeons. Supported by NIA.
  • Gleichmann M et al. (2012) Molecular changes in brain aging and Alzheimer’s disease are mirrored in experimentally silenced cortical neuron networks. National Institute on Aging. Supported by NIA.
  • Iijima-Ando K et al. (2009) Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer’s disease. Thomas Jefferson University, Philadelphia. Supported by NIA.
  • Sametsky EA et al. (2010) Synaptic strength and postsynaptically silent synapses through advanced aging in rat hippocampal CA1 pyramidal neurons. Northwestern University Feinberg School of Medicine. Supported by NIA.
 
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