FBPixel Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model - David Perlmutter M.D.


Study Title
Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model

Se Hoon Choi, Enjana Bylykbashi, Zena K. Chatila, Star W. Lee, Benjamin Pulli, Gregory D. Clemenson, Eunhee Kim, Alexander Rompala, Mary K. Oram, Caroline Asselin, Jenna Aronson, Can Zhang, Sean J. Miller, Andrea Lesinski, John W. Chen, Doo Yeon Kim, Henriette van Praag, Bruce M. Spiegelman, Fred H. Gage, Rudolph E. Tanzi


Alzheimer’s disease (AD) is the most common form of age-related dementia, characterized by cognitive impairment, neurodegeneration, b-amyloid (Ab) deposition, neurofibrillary tangle formation, and neuro- inflammation. The most popular therapeutic approach aimed at reducing Ab burden has not yet proved effective in halting disease progression. A successful therapy would both remove the pathological hallmarks of the disease and provide some functional recovery. The hippocampus contains neural progenitor cells that continue to generate new neurons, a process called adult hippocampal neurogenesis(AHN). AHN is impaired before the onset of classical AD pathology in AD mouse models. Human AHN has also been reported to be altered in AD patients. However, evidence sup- porting a role for AHN in AD has remained sparse and inconclusive.
RATIONALE: Two fundamental questions remain: (i) whether AHN could be enhanced and exploited for therapeutic purposes for AD, and (ii) whether AHN impairment mediates aspects of AD pathogenesis. To address these questions, we increased AHN genetically (WNT3) and pharmacologically (P7C3) in AD transgenic 5×FAD mice and explored whether promoting AHN alone can ameliorate AD pathology and behavioral symptoms. We assessed the role of exercise, a known neurogenic stimulus, and explored whether promoting AHN in conjunction with the salutary biochemical changes induced by exercise can improve AD pathology and behavioral symptoms in mice. We also investigated whether AHN suppression, by irradiation, temozolomide, or dominant- negative WNT, contributes to AD pathogenesis and assessed the functional roles of AHN in AD.
RESULTS: Inducing AHN alone conferred min- imal to no benefit for improving cognition in 5×FAD mice. Exercise-induced AHN improved cognition along with reduced Ab load and in- creased levels of brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), fibronectin type III domain–containing protein– 5 (FNDC5), and synaptic markers. However, AHN activation was also required for exercise-induced improvement in memory. Inducing AHN genetically and pharmacologically in combination with elevating BDNF levels mimicked beneficial effects of exercise on AD mice. Conversely, sup- pressing AHN in early stages of AD exacerbated neuronal vulnerability in later stages of AD, leading to cognitive impairment and increased neuronal loss. However, no such effects from AHN ablation were observed in nontransgenic wild-type (WT) mice, suggesting that AHN has a specific role in AD.
CONCLUSION: Promoting AHN can only ameliorate AD pathology and cognitive deficits in the presence of a healthier, improved local brain environment, e.g., stimulated by exercise. Increasing AHN alone combined with over- expression of BDNF could mimic exercise- induced improvements in cognition, without reducing Ab burden. Adult-born neurons generated very early in life are critical for maintaining hippocampal neuronal populations in the hostile brain environment created by AD later in life. Thus, AHN impairment may be a primary event that later mediates other aspects of AD pathogenesis. Future attempts to create pharmacological mimetics of the benefits of exercise on both increased AHN and BDNF may someday provide an effective means for improving cognition in AD. Moreover, increasing neurogenesis in the earliest stages of AD pathogenesis may protect against neuronal cell death later in the disease, providing a potentially powerful disease-modifying treatment

September 7, 2018
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Aerobic ExerciseBDNFAlzheimer’sExercise

Dr. David Perlmutter is on the cutting edge of innovative medicine that looks at all lifestyle influences on health and illness.

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