SuperAger brains contain ‘super neurons’
- Feinberg School of Medicine
Neurons in an area of the brain responsible for memory — known as the entorhinal cortex — were significantly larger in SuperAgers compared to cognitively average peers, individuals with early-stage Alzheimer’s disease and even individuals 20 to 30 years younger than SuperAgers, who are aged 80 years and older, reports a new Northwestern Medicine study.
These neurons did not harbor tau tangles, a signature hallmark of Alzheimer’s disease.
“The remarkable observation that SuperAgers showed larger neurons than their younger peers may imply that large cells were present from birth and are maintained structurally throughout their lives,” said lead author Tamar Gefen, an assistant professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. “We conclude that larger neurons are a biological signature of the SuperAging trajectory.”
The study of SuperAgers with exceptional memory was the first to show that these individuals carry a unique biological signature that comprises larger and healthier neurons in the entorhinal cortex that are relatively void of tau tangles (pathology).
The Northwestern SuperAging Research Program studies unique individuals known as SuperAgers, 80+ year-olds who show exceptional memory at least as good as individuals 20 to 30 years their junior.
“To understand how and why people may be resistant to developing Alzheimer’s disease, it is important to closely investigate the postmortem brains of SuperAgers,” Gefen said. “What makes SuperAgers’ brains unique? How can we harness their biologic traits to help elderly stave off Alzheimer’s disease?”
Scientists studied the entorhinal cortex of the brain because it controls memory and is one of the first locations targeted by Alzheimer’s disease. The entorhinal cortex comprises six layers of neurons packed on top of one another.Layer II, in particular, receives information from other memory centers and is a very specific and crucial hub along the brain’s memory circuit.
In the study, scientists show that SuperAgers harbor large, healthier neurons in layer II of the entorhinal cortex compared to their same-aged peers, individuals with early stages of Alzheimer’s disease and even individuals 20 to 30 years younger. They also showed that these large layer II neurons were spared from the formation of tau tangles.
Taken together, the findings suggest that a neuron spared from tangle formation can maintain its structural integrity (i.e., remain healthy and large). The inverse also seems to be true: Tau tangles can lead to neuronal shrinkage.
Participants in the SuperAger study donate their brains for research.
For the study, scientists examined the brains of six SuperAgers, seven cognitively average elderly individuals, six young individuals and five individuals with early stages of Alzheimer’s. Then they measured the size of neurons in layer II of the entorhinal cortex (compared to layers III and V). They also measured the presence of tau tangles in these cases.
For reasons that remain unknown, cell populations in the entorhinal cortex are selectively vulnerable to tau tangle formation during normal aging and in early stages of Alzheimer’s.
“In this study, we show that in Alzheimer’s, neuronal shrinkage (atrophy) in the entorhinal cortex appears to be a characteristic marker of the disease,” Gefen said.
“We suspect this process is a function of tau tangle formation in the affected cells leading to poor memory abilities in older age,” Gefen said. “Identifying this contributing factor (and every contributing factor) is crucial to the early identification of Alzheimer’s, monitoring its course and guiding treatment.”
Future studies are needed to understand how and why neuronal integrity is preserved in SuperAgers. Gefen wants to focus on probing the cellular environment.
“What are the chemical, metabolic or genetic features of these cells that render them resilient?” she asked. She also plans to investigate other hubs along the memory circuit of the brain to better understand the spread of or resistance to disease.
“We expect this research to be amplified and more impactful through a $20 million expansion of the SuperAging Initiative now enrolling five sites in the U.S. and Canada,” said Emily Rogalski, associate director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University Feinberg School of Medicine.
The study was published Sept. 30 in The Journal of Neuroscience.
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The mission of the Mesulam Center is to conduct cutting-edge research on the devastating neurodegenerative disorders that cause dementia. Through this research we seek to better understand the underlying biological mechanisms of dementias so that we may identify novel therapeutic targets for the amelioration of disease. Our mission is also to clarify the neural organization of behavior and cognition in the human brain and to offer our patients and their families personalized care that addresses the symptoms as well as the underlying disease.”
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Below are labs and faculty investigating neurological diseases that interfere with cognition and behavior from basic science to clinical, social and behavioral investigations.
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Bonakdarpour Lab Dr. Bonakdarpour’s lab uses multimodal neuroimaging to study the underlying neural mechanisms of language impairment (aphasia) and impairment in other areas of cognition.
For more information about the Bonakdarpour Lab, please visit the Bonakdarpour Laboratory website .
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Kahnt Lab Dr. Kahnt’s lab focuses on the neural and computational principles of reward-guided behavior.
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We study brain systems involved in learning, generalization and decision-making such as the striatum and the orbitofrontal cortex. For this, we use a combination of human psychophysics, computational models, fMRI and advanced multivariate analyses techniques borrowed from machine learning. This research may pave the way for understanding decision-making deficits in neurological diseases and should ultimately lead to novel diagnostic markers and treatment strategies for these disorders.
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For more information visit the faculty profile of Thorsten Kahnt, PhD , or visit the Kahnt Lab website .
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Thorsten Kahnt, PhD at 312-503-2896
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Mesulam Lab Dr. Mesulam’s lab studies Alzheimer's disease and related disorders.
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As the director of the NIH-funded Cognitive Neurology and Alzheimer’s Disease Center (CNADC), Dr. Mesulam’s research focuses on cognition and aging. The CNADC’s research ranges from evaluating quality-of-life interventions for Alzheimer’s disease, to understanding the underlying molecular mechanisms of neurodegenerative diseases, and everything in between. Many of the research studies at the CNADC are related to primary progressive aphasia (PPA), a rare dementia syndrome characterized by the progressive loss of language abilities with relative sparing of other areas of cognition. As one of the top referral centers for PPA in the world, they maintain a large cohort of patients who are thoroughly studied using a variety of techniques, including MRI, ERP, and neuropsychological testing. All research patients have the opportunity to participate in the Brain Donation Program, which allows researchers to understand the link between clinical presentation and underlying neuropathologic disease.
For more information please see the faculty profile of M Marsel Mesulam, MD or visit the The Cognitive Neurology and Alzheimer’s Disease Center (CNADC) website .
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Savas Lab The Savas lab aims to accelerate our understanding of the proteins and proteomes responsible for neurodevelopmental and neurodegenerative diseases.
We use biochemistry with discovery-based mass spectrometry to identify the protein perturbations which drive synaptopathies and proteinopathies. Groups of perturbed proteins serve as pathway beacons which we subsequently characterizes in hopes of finding new pathogenic mechanisms and potential future therapeutic targets.
For more information view the faculty profile of Jeffrey Savas, PhD or the Savas Lab website .
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Jeffrey Savas, PhD Assistant Professor in Neurology 312-503-3089
Vassar Lab Dr. Vassar’s lab is studying the role of Ab and BACE1 in normal biological processes and in disease mechanisms of relevance to Alzheimer’s disease.
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The progressive degeneration of neurons in regions of the brain important for cognition causes the dementia that slowly robs AD patients of their memories, personalities and eventually their lives.
AD pathology is characterized by two microscopic brain lesions:
- Amyloid plaques: Extracellular deposits of the beta-amyloid peptide (Ab), and the longer 42 amino acid form, Ab42, which is strongly associated with autosomal dominant forms of familial AD
- Neurofibrillary tangles
Ab is generated from the amyloid precursor protein (APP) by endoproteolysis from two proteases called the b- and g-secretases. The b-secretase, a novel aspartic protease termed BACE1, was initially cloned and characterized by our group (Vassar, et al., 1999). BACE1 is required for the generation of all forms of Ab, including Ab42, and therefore is a prime drug target for the treatment of AD.
Our ongoing research focuses on the role of Ab and BACE1 in normal biological processes and in disease mechanisms of relevance to AD, including:
- The functions of BACE1 and the homologue, BACE2 and the cell biology of Ab in neurons
- The role of inflammation in AD pathophysiology
- Novel transgenic and knockout mouse models of AD
- Molecular changes that may occur during brain aging leading to neurodegeneration
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Mesulam, M Marsel
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