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Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Autophagy Promotes Memory Formation Timir Tripathi,*,† Parismita Kalita,† Ralph Martins,‡,§ and Prashant Bharadwaj‡,∥
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Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Umshing, Shillong 793022, Meghalaya, India ‡ Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia § School of Biomedical Science, Macquarie University, Sydney, NSW 2109, Australia ∥ School of Pharmacy and Biomedical Sciences, Curtin Health and Innovation Research Institute (CHIRI), Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia ABSTRACT: Autophagy is traditionally known to be a stress response and a quality control mechanism for protecting cells from injury and disease. In addition to its housekeeping functions, autophagy also has specialized functions including regulation of synaptic activity and neurotransmission. Decreased autophagy is commonly associated with aging; however, the functional importance of autophagy in regulating cognitive function and its decline during aging were previously not known. A recent study showed that the induction of hippocampal autophagy improves cognition by enhancing memory formation and reverses memory decline during aging. Here, we discuss the findings of that study and explore the scope of the physiological process of autophagy in the development of treatments for age-related cognitive decline and neurodegenerative diseases. KEYWORDS: Autophagy, autophagosome, hippocampus, aging, synaptic plasticity, neurodegeneration, memory
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To understand the mechanisms underlying these processes, the authors used 3 month old mice and exposed them to novel memory stimuli. They found that both the protein and mRNA expression levels of autophagy-related proteins (ATGs) increased in order of the level of the stimuli. In addition, there was an increase in autophagosome (AP) formation and a decrease in AP cargo protein, indicating that the new memoryrelated stimulations increase the hippocampal autophagy flux. These suggest that autophagy is involved in the regulation of memory and learning in the hippocampus. The authors then analyzed if the hippocampal autophagy influences memory performances. Using shRNAs against AP biogenesis genes, they generated mouse models that cause selective downregulation of autophagy. In these mice, a decrease in the abundance of AP formation markers and an increase in AP cargo proteins upon shRNA introduction confirmed that the hippocampal autophagy was impaired and that cognitive fitness was compromised. Further, memory stimulation using behavioral tests showed that hippocampal autophagy is enhanced and that the learning and memory are specifically dependent on induced autophagy flux in hippocampal neurons. The next question was: with respect to the above processes, what are the neuronal consequences of hippocampal stimulation on autophagy? To address this question, the authors isolated primary hippocampal neurons from mice and stimulated them using chemical depolarization or chemical long-term potential, both of which can induce synaptic plasticity. They observed increased AP formation and increased synaptic strength. They also observed that the
utophagy is an intracellular catabolic process that helps in systematic degradation and continuous recycling of cellular components through a lysosome-dependent pathway. In general, it is usually stimulated during nutrient starvation and is associated with antiaging effects like increased lifespan and survival.1 Increasing basal autophagy positively modulates the lifespan of mammals by preventing premature aging, improving health, and promoting longevity.2 It has been shown that compounds that inhibit or activate autophagy disrupt or facilitate long-term memory, respectively.3 In the brain, the hippocampus plays an important role in the consolidation of memory and learning. This depends on the ability of the hippocampus to integrate new stimuli through neuronal plasticity at brain circuits. The hippocampus is extremely susceptible to aging, displaying functional alterations in neuronal structural organization and synaptic plasticity. It has been shown that the exposure of youthful systemic factors in aging brain can rescue, prevent, or reverse cognitive decline.4 However, the underlying mechanisms are poorly understood. Thus, it is important to understand the mechanisms involved in neuronal plasticity and memory in the hippocampus and the importance of autophagy in regulating cognitive function and its decline during aging. Recently, Glatigny et al. studied the role of autophagy in hippocampal-dependent cognitive fitness and revealed whether age-related impairment of brain autophagy is responsible for memory decline in the hippocampus.5 The authors showed that the induction of novel stimuli increases autophagy by fostering synaptic plasticity in hippocampal neurons. In addition, they showed that restoring autophagy levels in old hippocampi reverses memory deficits. The authors also revealed that autophagy could be activated by exposure of young circulating factors in the hippocampus. © XXXX American Chemical Society
Received: June 1, 2019 Accepted: June 4, 2019
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DOI: 10.1021/acschemneuro.9b00317 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. Model for neuronal autophagy during normal, aging, and diseased conditions. (A) Under homeostatic conditions in a young neuron, autophagosome (AP) formation is enriched in the distal axon and undergoes retrograde transport maturing into degradative autolysosomes. (B) During aging, there is an overall decline in AP synthesis, transport, and degradation, leading to decreased neuronal activity and synaptic function. (C) In diseased conditions, there is an increased accumulation of amyloidogenic proteins and dysfunctional organelles associated with defects in retrograde transport, maturation of lysosomes and AP, resulting in dystrophic axons and cell death.
link between autophagy and aging and suggest that promoting adaptive responses like autophagy may guide the development of treatments for memory decline in aging populations. In contrast to normal aging, age-related neurodegenerative diseases like Alzheimer’s disease (AD) display accumulation of amyloidogenic protein deposits associated with disruption of autophagy at various points along the pathway, giving rise to distinct pathologic patterns (Figure 1). Neurons are particularly vulnerable to accumulation of toxic amyloidogenic proteins and are heavily dependent on autophagy to maintain homeostasis because of their large expanses of axonal and dendritic cytoplasm that face particular hurdles in preventing the accumulation of damaged organelles and cellular waste. Although activating autophagy to promote removal of toxic amyloidogenic proteins has shown benefits in cell and animal models, studies caution the stimulation of this pathway during aging and in symptomatic disease, where there is pre-existing protein aggregation and associated impairment in autophagy. Therefore, it is recommended to selectively modulate autophagic activity for restoring intracellular homeostasis, removing protein aggregates, and reducing cell death so as to prevent age-related neurodegenerative diseases. Further analyses will, therefore, be required to determine the benefits of pharmacological induction of autophagy in repairing the defective transport and synaptic functions critical for memory formation.
induction of autophagy is essential to increase the activitydependent plasticity changes in hippocampal neurons during memory stimulation. All these data demonstrate that autophagy is essential to stimulate both functional and structural hippocampal synaptic plasticity upon stimulation of novel memories. Lastly, the authors tested whether promoting autophagy in old hippocampi can reverse age-impaired memory. They used 16 month old mice and observed that both the protein and mRNA expression level of the ATGs and AP formation markers decreased, while the AP cargo protein increased. They injected these mice with hippocampal stereotactic injections of TAT-beclin1, an autophagy inducer, to reverse age-impaired memory. They found that autophagy was induced in these mice and their memory was improved. These results suggest that inducing autophagy in old hippocampi can restore memory in aged mice. It has been reported that the administration of young systemic factors may rescue age-related impairments and improve cognitive function and synaptic plasticity in mice. The authors used osteocalcin, a circulating factor in young plasma, and observed that rejuvenating osteocalcin present in young plasma restored age-impaired memory loss via ameliorating autophagy levels in old hippocampi. Although the molecular mechanisms underlying the age-related loss of autophagy are yet to be determined, the present study provides a benchmark indicating that autophagy promotes memory formation and restores ageimpaired memory loss. While the study focused on hippocampal neurons, it did not examine whether the autophagy activity in other hippocampal cell populations and other cell types (e.g., astrocytes) may contribute to memory formation and cognitive fitness. The study of Glatigny et al. reinforces the
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AUTHOR INFORMATION
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DOI: 10.1021/acschemneuro.9b00317 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience ORCID
Timir Tripathi: 0000-0001-5559-289X Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acschemneuro.9b00317 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
