Researchers have identified a link between early and late-onset Alzheimer‘s disease
Amyloid-β (Aβ), which forms plaques that are believed to damage neuronal cells, is widely thought to be a major cause of Alzheimer‘s disease (AD). However, the causes of AD are not completely understood, and a link between early and late-onset AD has not been found. Recent research conducted at the Washington University School of Medicine (MO, USA) identified an additional cause of AD, as well as a connection between early and late-onset AD.
Guojun Bu and colleagues demonstrated that during Aβ synthesis, a small protein that regulates cholesterol levels in the brain is also released. “Our research links two major determinants for early and late-onset AD”, says Bu, senior author of the study. Furthermore, “…we‘ve shown that the process that links them is implicated in brain cholesterol metabolism”.
The study supports previous evidence for a role of cholesterol in AD pathogenesis. Earlier studies had suggested that statins, a class of drugs that are widely prescribed to lower cholesterol, may be neuroprotective in AD patients. However, other studies dispute this beneficial effect. “The studies of statins and Alzheimer‘s have generated quite a bit of controversy”, Bu explains. “Those that show positive effects from statins seem to suggest that high cholesterol could increase the risk of AD. But other evidence contradicts this idea”, he says.
Despite this, cholesterol does appear to be important in the brain. Approximately 20% of the body‘s cholesterol is found in the brain (a high proportion considering the brain accounts for only 2% of your body weight). “There is strong evidence that cholesterol is important for synaptic function and is an essential component of cell membranes in the brain, and I believe partial defects in the regulation of cholesterol metabolism in the brain likely contribute to the development of Alzheimer‘s”, explains Bu.
Early onset AD has been traced to mutations in one of three genes. One of these genes encodes the amyloid precursor protein (APP); in most cases, people with mutations in this gene develop AD at a relatively young age. Late-onset AD accounts for 95% of AD cases and has been linked to mutations in the ApoE gene.
In this study, it was shown that Aβ-plus, a small protein fragment, is released when APP is cleaved. Aβ-plus regulates ApoE, which transports cholesterol in the brain from support cells to neurons. It has previously been shown that the synapses are sensitive to cholesterol levels and altering cholesterol transport may cause loss of synapses.
“Cholesterol metabolism in the brain is an understudied area, and our findings could inspire Alzheimer‘s researchers to look further into the role of the cholesterol pathway”, Bu says. “Right now, research on Alzheimer‘s treatment focuses largely on reducing Aβ production or increasing its clearance from the brain. Our study suggests that there could be an alternate way to treat the disease, perhaps by modulating the function of ApoE and cholesterol in the brain”, he continues.
In the future Bu and colleagues hope to screen for compounds that could enhance cholesterol metabolism in the brain and thereby alleviate the symptoms of AD.
Source: Liu Q, Zerbinatti CV, Zhang J et al.: Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56, 66–78 (2007).
Minocycline may be effective in stroke treatment up to 24 h after symptoms begin
A study published in Neurology, the journal of the American Academy of Neurology, reports that minocycline treatment may be effective in the treatment of stroke, even when administered 24 h after the onset of symptoms. People treated with the drug between 6 and 24 h after a stroke had significantly fewer disabilities.
A total of 152 men and women received either an oral dose of minocycline or placebo for 5 days following stroke. Those administered minocycline were treated an average of 13 h following stroke, while those receiving placebo were treated at 12 h. Both groups were followed for three months.
Outcome was measured using the National Institutes of Health Stroke Scale (NIHSS). This measures facial palsy, movement, vision and speaking ability. The outcome was shown to be significantly better in patients receiving minocycline compared with placebo. At 3 months follow-up, the minocycline group performed four times better than the placebo group, with NIHSS scores of 1.6 and 6.5, respectively. A score of 1.6 indicates little or no disability, while a score of 6.5 is the high end of mild disability.
The study suggests that minocycline may be an alternative treatment for stroke, since the window for treatment with current drugs is very short. The time frame for treatment with minocycline appears to be longer and “…the improvement was already apparent within a week of the stroke”, explains Yair Laml (Edith Wolfson Medical Center, Israel). “This is exciting because many people who have had stroke cannot be treated if they don‘t get to the hospital within 3 h after symptoms start, which is the time frame for current available treatments”.
Lampl warns that “…while these are promising results, a much larger, closed-label, study is needed to confirm our findings … further research is also needed to look at whether the dosage of the drug taken in this study is optimal and whether giving the drug through an IV would be more effective”.
Minocycline‘s basic antibiotic effect is not thought to be responsible for the improvement; instead it is the anti-inflammatory and neuroprotective effect that is responsible.
Source: Lampl Y, Boaz M, Gilad R: Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69(14), 1404–1410 (2007).
Researchers identify potential new therapeutic approach for schizophrenia
In the October issue of Biological Psychiatry, Bita Moghaddam and colleagues (University of Pittsburgh, PA, USA) report evidence for a new treatment approach to schizophrenia.
Schizophrenia is a multifaceted condition considered to be one of the most devastating of the major psychiatric disorders. The three facets of schizophrenia are termed positive (hallucinations and delusions), negative (blunted emotions) and cognitive (memory, attention and problem-solving impairments).
Schizophrenia is currently treated with dopamine D2-receptor blockers. However, their efficacy in treating the negative and cognitive symptoms is limited. Moreover, they are frequently associated with significant side effects. “Hence, there is an acute need to develop alternative treatments for schizophrenia that have fewer side effects and are more effective in treating cognitive and negative symptoms of the disorder”, Moghaddam and colleagues explain.
The glutamate system has emerged as a promising therapeutic target in schizophrenia. It has been suggested that in the prefrontal cortex and hippocampus, in particular, glutamate-related circuit dysfunction may be associated with the cognitive symptoms of schizophrenia. A rodent model of this dysfunction can be created by blocking NMDA receptors.
It was demonstrated that the drug – cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) – stimulates the metabotropic glutamate receptor (mGluR)5 in the rat model and this normalized prefrontal cortical abnormalities. Therefore, it appears that CDPPB can treat brain abnormalities in a model that resembles schizophrenia.
Moghaddam says “…this work is significant because it shows that in an awake behaving mammal … activation of these receptors has a normalizing effect on the spontaneous activity of prefrontal cortex neurons”. John H Krystal (Yale University School of Medicine and VA Connecticut Healthcare System, CT, USA) comments “…these exciting new data provide important new evidence supporting the testing of mGluR5-stimulating medications for the treatment of schizophrenia, particularly cognitive deficits associated with impairments in the function of the prefrontal cortex”.
It would be very interesting to know whether this class of medication reduces the transient impairments in cognitive function associated with the administration of NMDA-receptor blockers to humans”.
Source: Lecourtier L, Homayoun H, Tamagnan G, Moghaddam B: Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Biol. Psychiatry 62(7), 739–746 (2007).
Neuroligin-3 mutant mouse model of autism spectrum disorders developed
A mouse model of autism spectrum disorders has been developed by researchers at Howard Hughes Medical Institute
Autism spectrum disorders (ASDs), which include conditions such as autism and Asperger syndrome, are cognitive disorders characterized by impaired social interactions that may be coupled with specialized cognitive abilities. In a small proportion of patients, autism has been linked with mutations in neuroligins. These proteins are cell adhesion molecules located in the synapse. Synapses are crucial to all brain activities, including thinking, behavior, memory and perception.
Researchers at Howard Hughes Medical Institute (University of Texas Southwestern Medical Center, TX, USA), have genetically engineered mice with an R451C mutation in the neuroligin-3 gene. This is the same mutation found in some people with ASDs and causes the mice to show a similar type of social impairment combined with cognitive enhancement. They believe that this represents an important advance in mouse models of ASDs and provides a new tool for researchers investigating neurodevelopmental defects.
A delicate balance between inhibitory and excitatory electrophysiological signaling exists in the properly functioning brain. In the mutant mice this balance was disrupted, increasing inhibitory neurotransmitters. By contrast, neuroligin-3 deletion did not cause an imbalance. The mutant mice also demonstrated impaired social interactions and enhanced spatial learning and memory.
“This combination of electrophysiological and behavioral effects is quite remarkable”, said Thomas Südhof. “It was also significant that these mice did not exhibit any other impairment of nervous system function – there was no abnormal locomotor activity or motor coordination, for example. This was a selective change, with social impairment on the one hand, yet cognitive enhancement on the other”.
The work is also significant because, as Südhof says, “…in mouse models of autism that I am aware of, the autistic symptoms are only one minor part of the overall disease. For example, autistic symptoms are only one component of mouse models of Fragile X syndrome”. The new mouse model would offer significant advantages over the existing models. “What sets this mouse model apart is that the mouse shows highly selective social deficits and memory enhancement, but as far as we can tell, no other pathologies. This makes it a potentially useful model for a subset of people with ASDs with just such characteristics”, he explains.
Südhof and colleagues will continue their work, studying the role of neuroligins in ASDs in greater detail. “We can also use these mice to study how these autistic symptoms – loss of social ability and enhanced memory – arise from the increase in inhibitory neurotransmission”, he said.
Source: Tabuchi K, Blundell J, Etherton MR et al.: A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318(5847), 71–76 (2007).