This is a very complex study, looking at how physical exercise might build protective effects against cognitive impairment in a genetic model of AD. The idea is that adult hippocampal neurogenesis plays a central role, at least as far as the hippocampus is concerned. The authors now show that combining a genetic enhancement of neurogenesis with the external application of BDNF can mimic the beneficial effects of exercise in terms of delaying or compensating the AD-like pathology and functional impairment. The study thereby nicely confirms that adult-generated neurons play a critical role in providing hippocampal resilience, and it suggests that exercise mimetics are indeed a possible route for preventive or therapeutic strategies. This speaks to the common quip, “If exercise were a pill, I would take it.”
Given its low cost and its essentially dearth of side effects, one might wonder whether in most cases simple physical activity is not the better choice, but conceptually the finding is of course very interesting. What one would have to look at is the context. AD does not only affect the hippocampus but adult neurogenesis is only found in the hippocampus, not in other cortical regions.
I think this is a carefully executed study that combines chemical and viral approaches to deliver neurogenic factors into the hippocampus for amelioration of cognitive decline and amyloid pathology in an established mouse model of β-amyloidosis.
This is one of the well-tested paradigms in clinical and preclinical studies: Exercise and adult neurogenesis supports cognitive maintenance and amyloid clearance. We have previously shown that AAV-mediated expression of FGF2 in the hippocampus in APP/PS1 mice enhances neurogenesis, hippocampal LTP, and spatial learning, while reducing amyloid load (Kiyota et al., 2011). Similar findings were observed upon AAV-mediated gene transfer of the anti-inflammatory cytokine IL-4 in the hippocampal region of APP/PS1 mice (Kiyota et al, 2010).
The new paper by Choi et al. elegantly shows that exercise or the combination of adult neurogenesis plus BDNF is necessary for the beneficial effect. The BDNF requirement could be due to the genetic difference between the 5xFAD they use and APP/PS1 mice, or due to the function of genes (P7C3, an NAMPT activator, and Wnt3a+BDNF vs. FGF-2). Validation of the key findings with additional AD mouse models is desirable. Since the study selected adult hippocampal neurogenesis (AHN) responder mice (ProAHN) from non-responders, one would wonder how successful this combination approach is for the induction of ProAHN, and if it could be improved to be 100 percent. It is also of interest to know how long the cognitive improvement can be maintained with this therapeutic approach.
It may be challenging to translate this finding to humans, since a recent paper shows a lack of adult hippocampal neurogenesis in people (Sorrells et al., 2018), although another lab reports its persistence throughout aging (Boldrini et al., 2018). This is a controversial field even now, and this study sheds new light on the potential therapeutic intervention using adult neurogenesis.
References:
Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T.
FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48.
PubMed.
Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T.
CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice.
FASEB J. 2010 Aug;24(8):3093-102.
PubMed.
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathern GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A.
Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.
Nature. 2018 Mar 15;555(7696):377-381. Epub 2018 Mar 7
PubMed.
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ.
Human Hippocampal Neurogenesis Persists throughout Aging.
Cell Stem Cell. 2018 Apr 5;22(4):589-599.e5.
PubMed.
Rumors that physical exercise might be able to counteract dementia (and also major depressive disorder, MDD) in a BDNF-dependent fashion have been rife in the field for more than 10 years. Nevertheless, a causal connection between physical exercise-induced increased BDNF level in the brain and amelioration of both diseases is still lacking. The Choi et al. paper now manages to provide more insights what this connection could be in AD.
Thus, the study provides several lines of evidence that adult hippocampal neurogenesis (AHN) and BDNF elevation, only together, can prevent the AD-related memory dysfunction at six months of age in transgenic mice that model the disease, if both manipulations have been started by two months after birth. They further show that BDNF elevation can only exert its beneficial effect against AD progression if AHN is not (artificially) blocked—a condition that usually does not occur anyway. Really compelling is the finding that genetic and pharmacological stimulation of AHN combined with pharmacologically (AICAR)-induced BDNF increase at 5.5 months can also ameliorate AD pathology.Last but not least, the authors provide independent data sets for male and female mice, showing mostly similar effects for both sexes.
Interesting as these findings are, the manipulations the authors employ represent a means to avoid or delay AD onset rather than a treatment strategy that could start close to or even after disease onset. Thus, future studies are of utmost importance that will address the following questions:
Can we find ways to increase brain BDNF levels:
… at later stages of AD progression to provide a therapy for patients who are already symptomatic?
… without prescribing aerobic exercise which is often not possible at older ages?
… without using rather invasive genetic manipulations required to provide artificial sources for AHN and BDNF?
Can the extremely low numbers of AHN-derived neurons in aged animals account mechanistically for AD amelioration alone?
Can combined action of AHN and BDNF elevation also restore reduced numbers of synaptic spines in pre-existing neurons, and counteract hyperexcitability and inefficient synaptic transmission of neurons, also known hallmarks of AD pathology?
What other (to be identified) running-associated increased growth factors and decreased cytokines team up with BDNF elevation to account for the beneficial effects of physical exercise in dementia?
Do we need to manipulate several drug targets simultaneously to ameliorate AD pathology, including therapies that avoid the pro-inflammatory actions and at the same time boost the protective effects of microglia?
Can antibody based therapies reducing the Aß burden in the brain even be revived as just one element of an effective combination therapy that tackles AD from many different angles?
Maybe we are currently heading into a new era in AD research that is defining and treating AD as a multifactorial systemic disease requiring a balanced multidrug and multi-treatment approach.
Comments
Center for Regenerative Therapies
This is a very complex study, looking at how physical exercise might build protective effects against cognitive impairment in a genetic model of AD. The idea is that adult hippocampal neurogenesis plays a central role, at least as far as the hippocampus is concerned. The authors now show that combining a genetic enhancement of neurogenesis with the external application of BDNF can mimic the beneficial effects of exercise in terms of delaying or compensating the AD-like pathology and functional impairment. The study thereby nicely confirms that adult-generated neurons play a critical role in providing hippocampal resilience, and it suggests that exercise mimetics are indeed a possible route for preventive or therapeutic strategies. This speaks to the common quip, “If exercise were a pill, I would take it.”
Given its low cost and its essentially dearth of side effects, one might wonder whether in most cases simple physical activity is not the better choice, but conceptually the finding is of course very interesting. What one would have to look at is the context. AD does not only affect the hippocampus but adult neurogenesis is only found in the hippocampus, not in other cortical regions.
View all comments by Gerd KempermannMayo Clinic Florida
I think this is a carefully executed study that combines chemical and viral approaches to deliver neurogenic factors into the hippocampus for amelioration of cognitive decline and amyloid pathology in an established mouse model of β-amyloidosis.
This is one of the well-tested paradigms in clinical and preclinical studies: Exercise and adult neurogenesis supports cognitive maintenance and amyloid clearance. We have previously shown that AAV-mediated expression of FGF2 in the hippocampus in APP/PS1 mice enhances neurogenesis, hippocampal LTP, and spatial learning, while reducing amyloid load (Kiyota et al., 2011). Similar findings were observed upon AAV-mediated gene transfer of the anti-inflammatory cytokine IL-4 in the hippocampal region of APP/PS1 mice (Kiyota et al, 2010).
The new paper by Choi et al. elegantly shows that exercise or the combination of adult neurogenesis plus BDNF is necessary for the beneficial effect. The BDNF requirement could be due to the genetic difference between the 5xFAD they use and APP/PS1 mice, or due to the function of genes (P7C3, an NAMPT activator, and Wnt3a+BDNF vs. FGF-2). Validation of the key findings with additional AD mouse models is desirable. Since the study selected adult hippocampal neurogenesis (AHN) responder mice (ProAHN) from non-responders, one would wonder how successful this combination approach is for the induction of ProAHN, and if it could be improved to be 100 percent. It is also of interest to know how long the cognitive improvement can be maintained with this therapeutic approach.
It may be challenging to translate this finding to humans, since a recent paper shows a lack of adult hippocampal neurogenesis in people (Sorrells et al., 2018), although another lab reports its persistence throughout aging (Boldrini et al., 2018). This is a controversial field even now, and this study sheds new light on the potential therapeutic intervention using adult neurogenesis.
References:
Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T. FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders. Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48. PubMed.
Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 2010 Aug;24(8):3093-102. PubMed.
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathern GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018 Mar 15;555(7696):377-381. Epub 2018 Mar 7 PubMed.
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ. Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell. 2018 Apr 5;22(4):589-599.e5. PubMed.
View all comments by Tsuneya IkezuOtto-von-Guericke-University
Rumors that physical exercise might be able to counteract dementia (and also major depressive disorder, MDD) in a BDNF-dependent fashion have been rife in the field for more than 10 years. Nevertheless, a causal connection between physical exercise-induced increased BDNF level in the brain and amelioration of both diseases is still lacking. The Choi et al. paper now manages to provide more insights what this connection could be in AD.
Thus, the study provides several lines of evidence that adult hippocampal neurogenesis (AHN) and BDNF elevation, only together, can prevent the AD-related memory dysfunction at six months of age in transgenic mice that model the disease, if both manipulations have been started by two months after birth. They further show that BDNF elevation can only exert its beneficial effect against AD progression if AHN is not (artificially) blocked—a condition that usually does not occur anyway. Really compelling is the finding that genetic and pharmacological stimulation of AHN combined with pharmacologically (AICAR)-induced BDNF increase at 5.5 months can also ameliorate AD pathology.Last but not least, the authors provide independent data sets for male and female mice, showing mostly similar effects for both sexes.
Interesting as these findings are, the manipulations the authors employ represent a means to avoid or delay AD onset rather than a treatment strategy that could start close to or even after disease onset. Thus, future studies are of utmost importance that will address the following questions:
Maybe we are currently heading into a new era in AD research that is defining and treating AD as a multifactorial systemic disease requiring a balanced multidrug and multi-treatment approach.
View all comments by Volkmar LessmannMake a Comment
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