The beta-amyloid hypothesis has dominated Alzheimer’s disease research for nearly 35 years. It proposes that plaques, comprised of the protein beta-amyloid, destroy synapses and stimulate the development of neurofibrillary tangles of the tau protein, which kills neurons in patients with the disease. Resultantly, neuroinflammation is triggered, which destroys more neurons and ultimately leads to dementia.
Thus far, the management of amyloid plaques in symptomatic patients has been the primary focus of interventions. However, to date, the treatments derived from this hypothesis have had no significant impact on the disease.
Research led by Rudolph E. Tanzi, PhD, co-director of the McCance Center for Brain Health and vice-chair of the Department of Neurology at Massachusetts General Hospital, and the late Robert D. Moir, PhD, argues that beta-amyloid may actually be part of a necessary neuroprotective system, first reported in 2010 in Plos One, and further described in, Neuron.
If validated, their idea, called the innate immune protection hypothesis, would require a fundamental reappraisal of Alzheimer’s disease etiology and treatment strategies.
The hypothesis is that the antimicrobial activities of Alzheimer’s disease hallmarks, beta-amyloid plaques and tau tangles, evolved into neuroprotective responses guarding against brain infection that then leads to neurotoxic consequences. Dr. Tanzi and Dr. Moir investigated this concept with research focused on brain infection that tested pathogens such as Salmonella and herpes viruses.
In Alzheimer’s and encephalitis mouse models, and three-dimensional human stem-cell culture models, microbial infection rapidly induces seeding of beta-amyloid deposits and tau tangles. This response protects against the herpes strains and bacterial pathogens in both models. However, this pathological process triggers the innate immune response of neuroinflammation, which causes extensive neuronal death.
Ultimately, the innate immune protection hypothesis suggests that treatment of Alzheimer’s disease patients should focus on curbing downstream neuroinflammation, while preventive measures in asymptomatic individuals should target the initial Alzheimer’s disease hallmarks, beta-amyloid plaques and tau tangles, to help delay or prevent the development of symptoms. Stopping microbes may serve as the primary prevention against the disease. Still, genetic factors contribute to risk for Alzheimer’s disease in any given patient. Dr. Tanzi’s laboratory is currently trying to identify the specific microbes that may trigger plaques and tangles in the brain.
“Amyloid deposits and the tau tangles they induce, may be normal functions of the primitive immune system of the brain. But, they are just the beginning of Alzheimer’s disease pathologies,” says Dr. Tanzi. “Downstream processes of neuroinflammation holds a key part of the puzzle and explains the bulk of neurodegeneration leading to dementia.”
Amyloid deposition is normally countered by microglial phagocytosis, which clears amyloid, cellular debris and dead neurons. But, Dr. Tanzi says, microglia switches function and kills neurons as amyloid induced tau tangles form. This reactive gliosis and neuroinflammation results in debilitating neural damage and dementia. Studies of so called resilient brains by Teresa Gomez-Isla, MD, chief of the Mass General Memory Disorders Unit, have shown that brains can contain abundant amounts of plaques and tangles. But without neuroinflammation, dementia is averted.
Dr. Tanzi’s primary focus is on identifying the genetic drivers that influence Alzheimer’s disease. He co-discovered all three early-onset familial Alzheimer’s disease genes, including the first Alzheimer’s gene making the beta-amyloid precursor protein. In 2008, Dr. Tanzi reported in the The American Journal of Human Genetics, the first Alzheimer’s gene associated with neuroinflammation in the disease, CD33. Subsequent research, published in Neuron by Dr. Tanzi and Ana Griciuc, PhD, associate professor in the Department of Neurology, showed that CD33, when highly expressed, turns the microglial response from protective to pathological, creating the runaway inflammation that is a distinguishing characteristic of Alzheimer’s dementia.
This discovery of the innate immunity genes associated with Alzheimer’s disease, combined with Dr. Tanzi’s and Dr. Moir’s antimicrobrial studies, suggests that the innate immune response is on a hair-trigger for decades before symptoms arise in people who carry genetic risk factors for the disease. Dr. Tanzi also believes Alzheimer’s disease gene mutations may have been conserved to protect the brain against infection when people lived in insanitary conditions.
Finding therapies that can target neuroinflammation is now considered key to controlling the progression of Alzheimer’s disease. “Symptomatic patients have built up decades of plaques and tangles, which ultimately trigger neuroinflammation and subsequent dementia due to neuronal death,” Dr. Tanzi says. “We have neuroinflammatory drugs in play for other neurodegenerative diseases, such as ALS, and what works for one inflammatory neurological condition should work for another.”
One example is a drug combination developed in 2014. The treatment, which is aimed at protecting neurons against inflammation, was recently announced to be successful in a clinical trial in patients with amyotrophic lateral sclerosis (ALS), led by Merit Cudkowicz, MD, MSc, chief of the Department of Neurology at Mass General, and director of the Healy Center for ALS.
Another example that Dr. Tanzi is studying is cromolyn. Originally used for asthma, his research group showed in a 2018 study published in Scientific Reports that the drug holds promise in impacting neuroinflammation. A reformulated version of cromolyn is in phase 3 clinical trials for Alzheimer’s disease treatment.
Finding drugs to target symptoms is a core goal in Alzheimer’s disease research. Equally important, though, is the work done on early interventions to disrupt the chronic neural damage that occurs before patients are aware of their condition. While innate immune response and genetic predisposition drive Alzheimer’s disease, integrative medicine concepts suggest that individuals genetically at risk for Alzheimer’s disease aren’t living with an inevitable dementia sentence.
Dr. Tanzi’s hypotheses integrate research that suggests that lifestyle interventions can help reduce Alzheimer’s disease pathologies. These interventions can combat plaque build-up and chronic inflammation, suppressing decades of neural damage.
“While we wait for effective drugs, we have the opportunity to help stave off Alzheimer’s disease with lifestyle and behavioral interventions,” Dr. Tanzi says. “Ultimately such interventions may be key elements in a chronic disease management approach.”
To promote adoption of preventive lifestyle measures, Dr. Tanzi developed a patient-friendly acronym, SHIELD. It defines key interventions that can be recommended to at-risk and symptomatic patients:
The innate immune protection hypothesis is a significant part of a fast-evolving body of evidence around Alzheimer’s disease, pointing researchers toward integrated and effective treatment of the inflammation that drives its debilitating symptoms. More importantly, early identification and prevention appear to be attainable goals.
Dr. Tanzi’s genetic research continues to hone understanding of the disease and reveal additional pathways to prevention and treatment. “Today’s 10-year-old child can reasonably look forward to routine screening for Alzheimer’s disease at age 40 or 50,” says Tanzi. “We’ll someday be able to effectively delay or even halt disease progression with lifestyle changes and pharmaceutical interventions.”
To read the article on the MGH website: https://advances.massgeneral.org/neuro/article.aspx?id=1129&utm_medium=social&utm_source=twitter&utm_campaign=FY20-neurosciences-immune-alzheimers