Scientists establish link between inflammatory process and progression of Alzheimer’s disease
An international team of researchers from the University of Massachusetts Medical School, the University of Bonn and the Center for Advanced European Studies and Research in Germany have shown that a well-known immune and inflammatory process plays an important role in the pathology of Alzheimer’s disease. This process, which results in the mature production of the pro-inflammatory cytokine called interleukin-1 beta (IL-1B) and is involved in the body’s defense against infection, has also been established as a clinical target for rheumatoid arthritis. The finding, published in Nature, points to the possibility that drugs that disrupt the production of IL-1B, such as those for rheumatoid arthritis, may also prove beneficial for patients with Alzheimer’s.
“This finding represents an important new clinical target for patients with Alzheimer’s disease,” said Douglas T. Golenbock, MD, chief of infectious diseases and immunology and professor of medicine and microbiology & physiological systems. “We’ve known for years that the plaques associated with Alzheimer’s were surrounded by microglia, the resident immune cell of the central nervous system. What we didn’t know was what role, if any, inflammation played in the progression of the disease. With this link we have a new path to potentially identifying and attacking this horrible disease.”
The most common form of dementia, Alzheimer’s is a degenerative neurological disorder that leads to memory loss, impaired cognitive function, and eventually death. By 2050 it is predicted that 1 in 85 people will suffer from Alzheimer’s disease. There are no available treatments.
A key physiological component of Alzheimer’s disease is the presence of extracellular plaques, primarily composed of beta amyloid peptides, which aggregate in the brain. These plaques are believed to be toxic and the chief cause of nearby neuron death and cortical material loss. The hippocampus, which plays an important role in short-term memory, is one of the first regions of the brain to suffer damage from Alzheimer’s.
Golenbock and colleagues had established in previous studies that neurons in cell cultures died after nearby microglia cells, the main form of active immune defense in the brain and spinal cord, were exposed to amyloid beta fibrils, such as those found in Alzheimer’s plaques. Typically, microglias are responsible for removing plaques, damaged neurons and infectious agents from the central nervous system. The beta amyloid peptide, however, generates inflammation in the central nervous system by activating microglia to produce neurotoxic compounds, including cytokines. How this process was being activated in patients with Alzheimer’s disease, though, was unclear.
Earlier work done in the Golenbock laboratory demonstrated that beta amyloid peptide could induce the production of IL-1B by activating a multi-protein receptor complex in microglial cells known as the NLRP3 inflammasome. Because of its ability to sense the beta amyloid peptide, the NLRP3 inflammasome has been implicated in several chronic inflammatory diseases, including gout and asbestosis. Examining Alzheimer’s tissue samples, scientists found that “every one of the cell samples contained increased evidence of activated inflammasomes, strongly suggesting that they were producing IL-1B,” said Golenbock.
What is Alzheimer’s disease?
Alzheimer’s disease is the most common form of dementia, a serious brain disorder that impacts daily living through memory loss and cognitive changes. Although not all memory loss indicates Alzheimer’s disease, one in ten people over 65 years of age, and over half of those over 85 have Alzheimer’s disease. Currently, 26 million people worldwide have this dementia, and over 15 million Americans will be affected by the year 2050.
Symptoms of Alzheimer’s disease usually develop slowly and gradually worsen over time, progressing from mild forgetfulness to widespread brain impairment. Chemical and structural changes in the brain slowly destroy the ability to create, remember, learn, reason, and relate to others. As critical cells die, drastic personality loss occurs and body systems fail.
Who is at risk of Alzheimer’s disease?
The primary risk factors of Alzheimer’s are age, family history, and genetics. However, there are other risk factors that you can influence. Maintaining a healthy heart and avoiding high blood pressure, heart disease, stroke, diabetes, and High cholesterol can decrease the risk of Alzheimer’s. Watch your weight, avoid tobacco and excess alcohol, stay socially connected, and exercise both your body and mind.
Early-onset Alzheimer’s affects patients under the age of 65. This relatively rare condition is seen more often in patients whose parents or grandparents developed Alzheimer’s disease at a young age, and is generally associated with three specific gene mutations (the APP gene found on chromosome 21, the PSI gene on chromosome 12, and the PS2 gene on chromosome 1).
“Taken together with our earlier studies, this strongly suggested a role for NLRP3 and caspase-1 in producing IL-1B leading to Alzheimer’s disease progression,” Golenbock said.
To assess the precise impact of NLRP3 and caspase-1 on Alzheimer’s disease in an organism, researchers recorded cognitive function and memory in mice models that expressed genes associated with familial Alzheimer’s but that were deficient in NLRP3 or caspase-1, and compared them with Alzheimer’s mice that had otherwise intact immune systems. When researchers performed memory recall tests of the Alzheimer’s in NLRP3- or caspase-1- mutant mice, they found the animals exhibited far better memory recall and appeared protected from memory loss. However, Alzheimer’s mice that expressed NLRP3 and caspase-1 at normal levels exhibited symptoms consistent with Alzheimer’s disease. Further examination revealed that NLRP3 and caspase-1 deficient mice showed a decrease in beta amyloid plaques and in increased ability of the microglia to remove fibrillar beta amyloid from the brain.
It was also revealed that activated IL-1 levels in the NLRP3 and caspase-1deficient mice were reduced compared to symptom-bearing counterparts. Because of NLRP3 and caspase-1 deficits, these mice produced less IL-1. These deficits appeared to promote formation of a microglia cell phenotype which was more capable of metabolizing and removing Alzheimer’s plaques from the central nervous system.
“These findings suggest that a knockout of NLRP3, caspase-1 or mature IL-1B may represent a novel therapeutic intervention for Alzheimer’s disease,” said Golenbock. “It’s possible that drugs that block NLRP3 or IL-1B – including some of which are already in clinical trials or on the market – might provide some benefit,” said Golenbock.
Why the name Alzheimer’s disease?
Aloysius Alzheimer was a German neuropathologist and psychiatrist. He is credited with identifying the first published case of “presenile dementia” in 1906, which Kraepelin later identified as Alzheimer’s disease - naming it after his colleague.
In 1901, while he worked at the city mental asylum in Frankfurt am Main, Germany, Dr. Alzheimer had a 51 year old patient called Mrs. Auguste Deter. The patient had distinct behavioral symptoms which did not fit any existing diagnoses - she had rapidly failing memory, disorientation, confusion, had trouble expressing her thoughts, and was suspicious about her family members and the hospital staff. Her symptoms progressed relentlessly. Dr. Alzheimer wrote that she once said to him “I have lost myself.”
Over the coming years Auguste Deter would take up more and more of Dr. Alzheimer’s time, to the point of almost becoming an obsession for him. The lady died in 1906 and Dr. Alzheimer, who was working at Kraepelin’s lab in Munich, had her patient records and brain sent there.
Along with two Italian doctors, Dr. Alzheimer performed an autopsy. The autopsy revealed that her brain had shrunken dramatically, but there was no evidence of atherosclerosis (thickening and hardening of the walls of the arteries). He used a silver staining technique he had learnt from ex-colleague Franz Nissl which identified amyloid plaques and neurofribrillary tangles in the brain - two hallmarks of the disease.
In November, 1906 Dr. Alzheimer gave the first lecture ever that presented the pathology and the clinical symptoms of presenile dementia together. Kraepelin started using the term Alzheimer’s disease, which by 1911 was being used throughout Europe and by European doctors when diagnosing patients in the USA.
Fairly recently, Dr. Alzheimer’s findings were reevaluated when his original microscope preparations on which he based his description of the disease were rediscovered in Munich.
A researcher from Prague, Oskar Fischer, and a contemporary of Dr. Alzheimer’s, may have described the pathology of dementia in greater depth than did Alzheimer himself, say Czech scientists who have been digging through historical archives in Prague.
“The critical part, though, is how much NLRP3 or IL-1B production can these drugs disrupt,” said Golenbock. “I believe that it’s not enough to block just 90 percent; it will probably have to be closer to 100 percent.”
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About the University of Massachusetts Medical School
The University of Massachusetts Medical School has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $250 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts.
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Jim Fessenden
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University of Massachusetts Medical School