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Smoking Cigarettes as a Potential Mechanism in Developing Alzheimer’s Disease
By Barry Nguyen, Biochemistry and Molecular Biology ‘23 & Vincent Tran Neurobiology, Physiology, and Behavior ‘23
Authors Note: During my study abroad in South Korea, I was taken back by the number of people smoking cigarettes in the streets. As a country that valued health and beauty, I was surprised by the frequent sights of civilians smoking cigarettes. I then realized that not many people are aware of the cognitive effects cigarettes may induce. We both wrote this review in hopes of spreading awareness of the link that many are not cognizant of.
Introduction
Alzheimer’s Disease (AD) is an irreversible neurodegenerative disease that is characterized by neuronal loss, memory impairment, and cognitive dysfunction (Wallin et al. 2017). It is the main form of dementia in the aging population and it has been projected to quadruple in the coming century. AD pathogenesis is caused by a variety of factors–smoking cigarettes being a very common environmental factor in today’s society. Cigarettes contain thousands of organic compounds that have the capacity to induce adverse health effects (Wallin 2017). Epidemiological studies strongly show cigarette smoking as an important risk factor in AD (Yuen-Shan Ho et al. 2012). Smoking cigarettes not only doubles the risk for developing cognitive disorders, but it also accelerates the rate of cognitive decline. Approximately 2 billion people worldwide use tobacco products, mostly in the form of cigarettes (Durazzo et al. 2014) and given the current projection of AD, it is becoming increasingly paramount to further investigate the relationship between smoking cigarettes and cognitive decline. In this review, we delineate 3 strongly supported mechanisms of tobacco use that manifest and contribute to AD pathogenesis, as well as discuss the societal factors that underlie individual differences in severity of AD symptoms.
Smoking-Associated Neurological Pathologies
Increased Cerebral Oxidative Stress
Maintaining the biochemical integrity of the brain is essential for its normal functioning. Oxidative stress (OxS), in addition to its capacity to onset various vascular pathologies (Chavez et. al, 2007), may also impair cerebral biochemistry (Salim 2017). Oxidative stress (OxS) is a phenomenon that is caused by free radicals, or chemical entities with an unpaired electron. Free radicals are common by-products of metabolic processes, and among which are reactive oxygen species (ROS) that have undergone a one electron reduction (Chavez et. al, 2007). When an excess amount of (ROS), reactive nitrogen species (RNS), and other oxidizing agents are produced (Durazzo et. al 2014), and the antioxidant system is unable to keep up with such radical formation, oxidative stress occurs (Salim 2017). In general, the resulting physiological pathologies include modification of biomolecules, which results in defective cellular signaling and accumulation of malfunctioned proteins. With this cascade of negative events induced by OxS, the imbalance between production and detoxification of ROS can have serious consequences on many of our physiological systems, and in particular, the brain.
Cigarettes are composed of approximately 5,000 combustion products and contain high concentrations of free radical species (Durazzo et. al 2017). Smoking inhibits the synthesis of antioxidant species, thereby propagating free radical formation and the consequences of oxidative stress. The human brain, in particular, is vulnerable to OxS damage due to its high metabolism and relatively low antioxidant enzymes. With this said, smoking cigarettes may have profound consequences on the brain.
To detect oxidative stress in the brain and its differential manifestations among smokers and nonsmokers, scientists divided a group of 9 male rats into two groups: four in the control and five in the cigarette smoking group (Ho et. al 2012). The rats in one group were exposed to sham air, or “clean air” to serve as the control while the rats in the experimental group were exposed to cigarette smoke for one hour a day for 56 days. After 56 days, the rats were euthanized and brain tissue was retrieved.
Figure 1. Anti-8-OHG antibody was used to visualize the levels of oxidative stress present in the hippocampus (Ho et. al 2012).
To detect levels of oxidative stress, researchers used anti-8-OHG, an antibody that stains biomarkers of oxidative stress and looked at regions in the brain responsible for memory. 8-hydroxy-2 deoxyguanosine (8 OHDG) and 8-hydroxyguanosine (8-OHG) are OxS biomarkers generated when guanine, a nucleotide present in DNA and RNA, is oxidized by reactive free radicals. In the IHC stainings, a higher fluorescence was observed among the experimental group as compared to the control, suggesting smoking cigarettes as a potential inducer in cerebral oxidative stress. Rats exposed to smoking show a significant immunoreactivity of 8-OHG in the dentate gyrus, which is a region in the brain responsible for memory (Fig. 1a and b), and CA3 (Fig. 1C and D) as compared to rats in the control group. The immunoreactivity of 8-OHG in the experimental group suggests that smoking does indeed induce oxidative stress by oxidizing the guanine nucleotide present in the DNA.
Decreased Expression of Synaptic Proteins
Synapsins are synaptic proteins that are essential for the normal functioning of the brain (Yuen-Shan Ho 2012). Synapsins belong to a family of phosphoproteins and are important for synapse development, neurotransmitter regulation, and nerve terminal formation (Mirza 2018). Current Alzheimer’s literature reveals a substantial involvement of malfunctioned synapsins in the development of AD. Namely, synaptic loss in the neocortex and limbic system, both regions important for higher order functions such as emotional responses, cognition, and spatial reasoning, may be responsible for the cognitive alterations in Alzheimer’s patients. Additionally, disturbances in synapsin homeostasis have revealed cognitive deficits and defective neurotransmitter transmission in Alzheimer’s patients (Lin et. al 2014).
In the same experiment investigating cigarettes’ capacity to induce neurological dysfunction, scientists observed a decreased expression of Synapsin 1, one of three isoforms of the protein (Ho et al. 2012). Using immunohistochemistry, the smoking group showed a reduction of fluorescent intensity, inferring decreased expression of Synapsin 1. These results further bolster the capacity of tobacco use in its contribution to AD pathogenesis due to the significance reduction in the Synapsin 1 protein as observed in the results. Furthermore, cigarettes’ ability to induce small scale pathological changes in the brain suggests its domino-like effect on cognitive function.
Figure 2. Immunohistochemical staining reveals significant reduction in Synapsin 1 protein between the control and smoking group (Ho et al. 2012).
Abnormal Phosphorylation of Tau Proteins
Tau pathology, a hallmark of Alzheimer Disease pathology, manifests due to the abnormal phosphorylation of Tau protein (Neddens 2018). This hyperphosphorylation of Tau results in Tau aggregation and are collectively known as neurofibrillary tangles (NFT), a histopathological marker for AD (Miao 2019). Oxidative stress in particular has a capacity to promote Tau pathology due to its fatty acid product which provides a direct link to mechanisms that induce NFT formation (Liu 2015). The mechanism in which OxS plays in the phosphorylation of Tau and subsequent aggregation is dependent on the type of oxidant and the specific amino acid sequences involved (Federica et. al 2019). For example, oxidation of cysteine residues have been observed to be involved in Tau aggregation, suggesting the phenomenon to be a disulfide bond mediated process.
Evidence linking oxidative stress and Tau hyperphosphorylation can be supported in an experiment utilizing Buthionine Sulfoximine treatment, which induces oxidative stress in M17 neuroblastoma cells (cancers of nerve cells) by inhibiting the synthesis of glutathione, a chemical important in the maintenance of the ROS equilibrium. Researchers were able to link HO-1, an oxidative stress biomarker, with an increase in hyperphosphorylation of PHF-1 sites. PHF sites, or paired helical filaments, are the structural constituents of neurofibrillary tangles, a pathological hallmark of AD. Taken together, smoking related OxS may serve as a fundamental mechanism in the pathogenesis of AD and indirectly influence AD pathogenesis by propagating the formation of NFT (Durazzo et. al 2014).
Possible Determinants of AD Differential Manifestations
As devastating as Alzheimer’s disease can be, the extent of its harm varies across a wide spectrum, and some people face greater damage or faster onset than others. Such variations in Alzheimer’s effects might be linked to not just biological but also environmental factors. As such, societal differences in the population can underpin the impact that various effects have on patients’ lifestyle and functioning with Alzheimer’s. This idea that Alzheimer’s effects are dependent on an individual basis is centered around an individual’s reserve against Alzheimer’s and other forms of dementia. Reserve against the effects of brain damage refers to the potential to alleviate dementia symptoms and progression and is further categorized into brain reserve and cognitive reserve.
Brain Reserve and Educational Attainment’s Connection to AD
Brain reserve describes how a larger amount of brain mass could offset the amount of damage that it would take for brain function to start being impaired. As patients afflicted by neurodegenerative diseases like Alzheimer’s could potentially lose more neurons and synapses before onset of clinical symptoms, those with larger brains could have better mitigation against symptoms of dementia (Bartrés-Faz et. al, 2011). With smoking linked to Alzheimer’s development, smokers could likely be diminishing the brain mass that would be buffering the rate at which neurological decay leads to impairment of memory and everyday functions.
Variations in individuals’ brain reserve could be associated with and predicted by individuals’ lifetime educational attainment. As such, a study using structural MRI analysis compared regional cortical thickness among a sample of individuals with different educational attainment. Those with more years of education were found to have larger regional cortical thickness, which was used to compare differences in brain size (Liu et al., 2012). This positive correlation between education level and cortical thickness demonstrates the positive impact of further education on development of more brain reserve.
Cognitive Reserve and Educational Attainment’s Connection to AD
Cognitive reserve is the concept that differences in learned cognitive processes can help the brain compensate for damage or dysfunction by relying on different functional approaches. As cognition for each individual relies on different recruitment patterns of neurons and synapses, individuals with more extensive neural networks would be more likely to compensate for the loss of neurons in a network vital for specific cognitive tasks (Bartrés-Faz et. al, 2011). Therefore, the same amount of brain damage to two individuals with similar brain sizes and physiologies could potentially result in differing effects in their functioning, due to differences in cognitive reserve.
Furthermore, differences in cognitive reserves can be attributed to lifetime educational or occupational levels, with epidemiological studies showing that individuals with less than 8 years of education have a significantly higher chance of dementia (Stern, 2012).
Access to educational opportunities has been unequally distributed across socioeconomic lines, with higher education’s high costs making it significantly more accessible to the middle and upper classes. Furthermore, there has also been a disparity in the racial distribution of Alzheimer’s in the U.S., with African Americans having the highest prevalence of AD followed by Hispanic Americans.
With smoking already presented as a risk factor for Alzheimer’s, its risk is compounded by the lessened reserve that is associated with education. Demographic studies demonstrated an inverse association between chances of smoking and educational attainment, with those who have less years of education being more prone to starting (Maralani, 2013). With those who smoke likely to have less education, such individuals would increase physiological risks of acquiring AD while also being more susceptible to developing AD at an earlier time.
Conclusion
Although smoking has been known to be the root perpetrator in a multitude of health risks and diseases, its effect on neurological health warrants increased scientific and public attention. As Alzheimer’s remains without a definite cure, current treatments revolve around managing symptoms and prevention of risk factors. With how smoking involves increased cerebral oxidative stress, decreased expression of synaptic proteins, and abnormal phosphorylation of Tau proteins, recent findings reiterate the necessity of avoiding smoking cigarettes to minimize further risks of developing AD. In the case that Alzheimer’s does develop in individuals, they can have a higher quality of life living with symptoms depending on their educational history, reiterating society’s need for better access to education.
Smoking cigarettes can produce 3 substantive effects that may contribute to the pathogenesis of AD: affecting synaptic proteins, increasing oxidative stress, and raising levels of hyperphosphorylated Tau protein.
References:
- Bartrés-Faz, D., & Arenaza-Urquijo, E. M. (2011). Structural and functional imaging correlates of cognitive and brain reserve hypotheses in healthy and pathological aging. Brain Topography, 24(3-4), 340–357.
- Durazzo, T., Mattsson, N., & Weiner, M. 2014 Smoking and Increased Alzheimer’s Disease Risk: A Review of Potential Mechanisms. Trauma Spectrum Disorder and Health Behavior 10:122-145
- Durazzo, T., Korecha, M., Trojanowski, J., Weiner, M., O’Hara, R., Ashford, J., & Shaw., L Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer’s Disease Is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. Journal of Alzheimer’s Disease 54: 99-107.
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- Ho, Y., Yang, X.,Yeung, S., Chiu, K., Lau, C., Tsang, A., Mak, J., & Chang, R. Cigarette Smoking Accelerated Brain Aging and Induced Pre-Alzheimer-Like Neuropathology in Rats. PLos ONE:7.
- Lin. L., Yang, S., Chu, J., Wang, L., Ning, L., Zhang, T., Jiang, Q., Tian, Q., & Wang, J. Region-Specific Expression of Tau, Amyloid-B Protein Precursor, and Synaptic Proteins at Physiological condition or Under Endoplasmic Reticulum Stress in Rats. Journal of Alzheimer’s Disease 41:1149-1163
- Liu, Y., Julkunen, V., Paajanen, T., Westman, E., Wahlund, L.-O., Aitken, A., Sobow, T., Mecocci, P., Tsolaki, M., Vellas, B., Muehlboeck, S., Spenger, C., Lovestone, S., Simmons, A., & Soininen, H. (2012). Education increases reserve against Alzheimer’s disease—evidence from structural MRI analysis. Neuroradiology, 54(9), 929–938.
- Maralani, V. (2013). Educational inequalities in smoking: The role of initiation versus quitting. Social Science & Medicine, 84, 129–137.
- Miao, J. Shi, R., Li, L., Chen, F., Zhou, Y., Tung, Y., Hu, W., Gong, C., Iqbal, K., & Fei, L. Pathological Tau From Alzheimer’s Brain Induces Site-Specific Hyperphosphorylation and SDS-and Reducing Agent-Resistant Aggregation of Tau in vivo. Frontiers in Aging Neuroscience 11: 34.
- Mirza, F. & S. Zahid. The Role of Synapsins in Neurological Disorders. Neuroscience Bulletin 34:349-358.
- Neddens, J., Temmel, M., Flunkert, S., Kerschbaumer, B., Hoeller, C., Loeffler, T., Niederkofler, V, Daum, G., Attems, J., & Paier, B. Phosphorylation of Different Tau Sites During Progression of Alzheimer’s Disease. Acta Neuropathol Commun 6.
- Salim, S. Oxidative Stress and the Central Nervous System. Journal of Pharmacology and Experimental Therapeutics 360:201205.
- Stern, Y. (2012). Cognitive Reserve in aging and Alzheimer’s disease. The Lancet Neurology, 11(11), 1006–1012.
- Wallin, C., Sholts, S., Osterlund, N., Luo, J., Jarvet, J., Roos, P., Llag, L., Graslund, A. & Warmlander, S. Alzheimer’s disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation. Scientific Reports 7.
The Role of Microglia in the Two Hallmarks of Alzheimer’s Pathology
By Nathifa Nasim, Neurobiology, Physiology, and Behavior ‘22
Author’s note: While in the Jin lab at the MIND Institute, I was introduced to the intersection between inflammation and neurodegeneration, specifically in the context of Alzheimer’s disease. My interest in this relationship has primarily been in manipulating inflammatory pathways to investigate the effects on the disease. However, I wanted to step back and understand how they connected, and compile a review on microglial activation as a bridge between the two.
Introduction:
Alzheimer’s, the most common form of dementia, is a neurodegenerative disease characterized by progressive loss of memory and cognitive function. It is still largely untreatable: the last drug approved by the FDA was released nearly two decades ago. Currently, there are only a few available treatments, all of which deal with alleviating symptoms rather than affecting any of the underlying pathology [1]. There are two primary hallmarks of Alzheimer’s disease: amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are formed from aggregations of small amyloid beta protein (Aβ); these amyloid beta are the product of cleavage of amyloid precursor proteins found in the membrane of neurons. Neurofibrillary tangles, on the other hand, form from tau protein, which stabilize neuronal microtubules and therefore allow for transport from the cell body to other parts of the neuron. Hyperphosphorylation of tau (a signaling mechanism) leads tao its detachment from the microtubule and aggregation into neurofibrillary tangles [2, 3].
Both amyloid plaques and NFTs are implicated in neurodegeneration and cognitive loss. Amyloid plaques are thought to be precursors that trigger a cascade culminating in neurodegeneration. On the other hand, the loss of support for microtubules in NFTs leads to impaired axonal transport, resulting in synaptic loss and neuronal dysfunction in an Alzheimer’s brain [2]. This review will explore an emerging aspect of Alzheimer’s research, microglial activation, as a means of mitigating both of these pathological characteristics of the disease thereby providing a potential avenue for approaching treatment.
The Role of Microglia:
In order to approach microglial activation, it is necessary to establish neuroinflammation’s role in neurodegeneration. Neuroinflammation refers to the central nervous system’s immune response, activated in response to trauma, pathogens, or the amyloid protein aggregations of Alzheimer’s, among others [2, 4]. It is a necessary immune response, but an overactive or continuous inflammatory response can be harmful, as evident in the body’s release of anti-inflammatory mediators alongside pro-inflammatory cytokines [2, 4]. Proinflammatory cytokines (proteins that are critical for immune signaling) such as IL-1β, IL-6, IL-18 and tumor necrosis factor (TNF), have various adverse effects on neuronal function including neuronal death, synaptic loss, and synaptic “pruning” or stripping [2, 5]. Therefore, unmitigated neuroinflammation can drive neurological disease, and is implicated in the pathology of all neurodegenerative diseases [4].
The main instruments of neuroinflammation are microglia: non-neuronal phagocytic cells that are the primary proponents of the brain’s immune response. Microglia recognize potential pathogens or irritants through receptors, and in response phagocytose and/or degrade the irritant while releasing cytokines, chemokines and interferons, immune signaling proteins [2]. There are two microglial activation states which dictate the inflammatory response: the “M1” or pro-inflammatory state associated with exacerbating neurodegeneration, and the “M2” or anti-inflammatory state [2, 4]. It must be noted that this binary is simplified, and currently under research. The overactivation of the inflammatory response can be linked to the M1 state of microglia. When inflammatory mediators such as IL-1β were released by microglia, they amplify the inflammation by activating more microglia, creating a positive feedback loop of neuroinflammation characteristic of a diseased state.
Based on their role in neuroinflammation, researchers have looked to microglia as key players in Alzhiemer’s pathology. Numerous research studies have indicated that microglial activation is increased in Alzheimer’s by observing increased expression of microglial receptors in the diseased brain [3, 6]. An example of this is a study that utilized [11C](R)-PK11195, a carbon labeled ligand specific to phagocytic cells. The ligand’s specificity to microglia was increased, allowing it to serve as an indicator for microglial activation. They found a significant increase of microglial activation in Alzheimer’s patients. Furthermore, the pattern of microglial activation physically mirrored the disease’s progress in the brain in terms of atrophy, among other indicators [5]. The research is supported by previous studies as well, all of which suggested that microglial activation is an early event in neurodegeneration, as it was present in mild/early cases of Alzheimer’s [3, 5]. The immune response appeared to escalate into causing more damage as the disease progressed [3].
Amyloid Plaques:
Decades-old research has confirmed the involvement of microglia in Alzheimer’s by demonstrating that microglia cluster around amyloid plaques. There is a progressive increase of activated microglia closer to dense plaque buildup, as well as a linear increase of activated microglia as overall plaque numbers increase [7]. As previously mentioned, amyloid precursor protein splicing leads to a beta amyloid protein; a derivative of the splicing, sAPP-α, has been shown to activate microglia. As microglia are activated by irritants, this falls in line with the general defense role of microglia. The sAPP-α protein, especially an Alzheimer’s-causing isoform which is more likely to aggregate, acts as a threat and thereby activates microglia. As an assumed consequence of the microglial activation, the same study verified that the presence of sAPP-α also increased inflammatory protein expression [8].
Tau Protein Involvement:
In addition to amyloid plaques, microglia have more recently been linked to the other hallmark of AD, neurofibrillary tau tangles. Similar to amyloid plaques, a linear pattern between NFT’s and activated microglia has also been shown [7]. Further supporting this connection, experimental depletion of microglia has led to decreased tau propagation [9]. Interestingly, although inflammatory mediators observed in one study were increased in patients with tau tangles and neurodegeneration, this was not the case in patients with only amyloid plaques. This highlights the importance of tau in microglial activation, as well as the difference in microglial relations between the two [3].
The interconnection between microglia and tau is proposed to be due to microglial phagocytosis of damaged neurons containing misfolded tau. The tau is secreted in exosomes, and these “seeds” of misformed tau protein are capable of inducing other tau to misfold and aggregate [6, 9, 10]. Although the exact mechanism of microglia engulfing tau is unclear, this theory fits with the overall degenerative pathology of Alzheimer’s in that microglia “prune” already damaged neurons and then engulf them. This increased tau phagocytosis and consequent release of misfolded tau increases overall NFTs, thereby further aggravating the disease state.
Tau, Amyloid and Microglia:
Microglia may also play a role in the pattern of tau accumulation and growth in the Alzheimer’s brain. Typically, as the disease progresses, NFTs “grow” in specific patterns or stages, culminating in the neocortex, the part of the brain devoted to higher cognitive functioning. This accumulation of plaques and NFTs in the neocortex is theorized to be the cause for dementia [6]. The propagation of tau, however, is still not fully understood—research is being conducted on whether microglial activation could be a cause. The current understanding of Alzheimer’s pathology via the amyloid cascade hypothesis suggests that amyloid plaques precede other aspects of Alzheimer’s pathology and neurodegeneration, and that tau tangles occur as a result of the “cascade” [2]. However, a recent study proposed that microglia could be the key player in this cascade. Microglia are theorized to act on Aβ, thereby increasing tau propagation, although they are not directly implicated in tau spread. Studies have shown a correlation between activated microglia with the development of cognitive impairment and dementia, supporting the theory that microglia are responsible for the tau propagation patterns seen as AD progresses [6]. This bridge between tau and amyloid via microglia-driven inflammation is further elucidated by another study. Researchers propose that microglial activation, intended to clear amyloid, additionally activates kinase pathways, specifically p38MAPK, directly/indirectly increasing tau phosphorylation, leading to neurofibrillary tangles [11].
Figure 1. In the healthy neuron, tau stabilizes the neuron, but in the diseased state, the phagocytosis of misfolded tau culminates in the formation of more tau misfolding when it is released. For amyloid, specific cleavage sites result in oligomers prone to aggregation which ideally is phagocytosed by the microglia
Potential Influence on Treatment:
Based on the role of microglia in immune activation and its implication in Alzheimer’s pathology, inhibition of microglial activation could theoretically be neuroprotective against the disease, among other neurodegenerative diseases in which neuroinflammation plays a key role. Research published earlier this year expanded on this idea. Based on increased expression of a receptor in activated microglia found in Parkinson’s, a neurodegenerative disease similar to Alzheimer’s in that it is also marked by cognitive deficits, the researchers proposed utilizing the agonist NLY0. Not only did the administration of the agonist block microglial activation, it also reduced inflammatory mediators that in turn activate astrocytes, another glial cell, preventing the cycle of neuroinflammation to neurodegeneration. There were also reduced Aβ plaque numbers in an Alzheimer’s model, and perhaps as a result, improvements in cognition such as improved memory [1].
Conclusion:
Alzheimer’s disease is characterized by inflammation, through which microglia, as proponents of the brain’s immune response, are implicated in the development of the disease. The two main hallmarks of the disease — amyloid plaques and neurofibrillary tangles — are both associated with increased levels of activated microglia. However, in both cases, it is difficult to determine whether increased microglia are present as a result of neurodegeneration or whether they contribute to neurodegeneration. Nonetheless, emerging research places microglia as an important component of the amyloid cascade, by which Aβ and NFTs are connected. Neuroinflammation triggered by the need to clear amyloid plaques may lead to hyperactive kinase activity, hyperphosphorylating tau and leading to NFTs.
Given microglial involvement, further research is needed to investigate the potential of microglial inhibition in the treatment of Alzheimer’s, amongst other neurological diseases. However, the established interplay between microglia and Alzheimer’s pathology provides an important avenue in which to investigate related treatment options while illuminating the connection between inflammation and neurodegeneration.
References:
- Park JS, Kam TI, Lee S, et al. 2021. Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease. acta neuropathol commun 9 (78). doi:10.1186/s40478-021-01180-z
- Leng F, Edison P. 2021. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol 17, 157–172. doi:10.1038/s41582-020-00435-y
- Nordengen K, Kirsebom BE, Henjum K, et al. 2019. Glial activation and inflammation along the Alzheimer’s disease continuum. J Neuroinflammation 16 (46). doi: 10.1186/s12974-019-1399-2
- Edison P, Donat CK and Sastre M. 2018. In vivo Imaging of Glial Activation in Alzheimer’s Disease. Front. Neurol. 9:625. doi:10.3389/fneur.2018.00625
- Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB. 2001. In-vivo measurement of activated microglia in dementia, The Lancet, 358 (9280): 461-467. doi:10.1016/S0140-6736(01)05625-2.
- Pascoal TA, Benedet AL, Ashton NJ, et al. 2021. Microglial activation and tau propagate jointly across Braak stages. Nat Med 27, 1592–1599. doi:10.1038/s41591-021-01456-w
- Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT. 2011. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. The American journal of pathology, 179(3): 1373–1384. doi:10.1016/j.ajpath.2011.05.047
- Barger S, Harmon A. 1997. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388: 878–88. doi:10.1038/42257
- Asai H, Ikezu S, Tsunoda S, et al. 2015. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18: 1584–1593. doi:10.1038/nn.4132
- Hopp SC, Lin Y, Oakley D, Roe AD, DeVos SL, Hanlon D, Hyman BT. (2018). The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. Journal of neuroinflammation, 15(1): 269. doi:10.1186/s12974-018-1309-z
- Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O’Banion MK. 2013. Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(11): 5053–5064. doi:10.1523/JNEUROSCI.4361-12.2013
Clearing the Cellular Landfill: The Use of Chaperone-Mediated Autophagy to Treat Alzheimer’s Disease
By Reshma Kolala, Microbiology, ‘22
Author’s Note: Alzheimer’s disease is one of the most common neurodegenerative disorders, affecting nearly 1 in 9 individuals aged 65 or older. Available current therapies fail to address the underlying pathophysiology of the disorder, focusing on the amelioration of neuronal symptoms that result from Alzheimer’s disease. I was immediately intrigued by the proposal that an existing mechanism for cellular waste removal, chaperone mediated autophagy, could be reinvigorated to remove toxic protein aggregates that are characteristic of an Alzheimer’s diagnosis, thereby targeting a significant contributing factor to the disease. This finding paves the way for new therapies that prevent or delay the onset of Alzheimer’s disease.
“Imagine someone has taken your brain and it’s an old file cabinet and spread all the files over the floor, and you have to put things back together,” describes Greg O’Brian, an award-winning political writer who was diagnosed with Alzheimer’s Disease in 2010. The disorienting feeling described by O’Brian in an interview with Medical Daily is familiar for those diagnosed with Alzheimer’s disease. “My former life no longer exists, and it’s up to me to create a new life,” explains Chris Hannafan in an interview with PBS Newshour, a year after his Alzheimer’s diagnosis. Alzheimer’s disease is a progressive brain disorder that leads to memory loss, developmental disabilities, and cognitive impairment. The cause of the disorder appears to be a culmination of a variety of complex factors that arise as we age, such as the degeneration of neuronal pathways, immune system dysfunction, the buildup of β-amyloid protein, among others [1]. Due to its composite nature, a cure for the neurodegenerative disorder continues to elude the scientific community and treatment remains focused on palliative care, medical care that is focused on relieving and mediating the symptoms of the disorder.
Of the several factors that contribute to an Alzheimer’s diagnosis, scientists have recently focused on a cellular process known as chaperone-mediated autophagy (CMA). Autophagy is a critical and versatile cellular mechanism that allows our cells to degrade or eliminate any unnecessary or damaged components [2]. “Without autophagy, the cell won’t survive,” notes Juleen Zierath, a physiologist at the Karolinska Institute in Stockholm, in an interview with Nature. The autophagy process may vary in each cell and is tailored to meet the demands of a specific cells’ workload. CMA refers to a specific form of autophagy that maintains the delicate balance of proteins in the brain through the use of chaperones. Chaperones or cellular “helpers,” lock onto faulty proteins to prevent buildup before being degraded by the cell. Similar to other cellular processes in our body, CMA is naturally less efficient as we age. This may be attributed to the accumulation of dysfunctional proteins and a compromised ability to respond to stressors over time [2]. When the age-dependent decline of CMA is paired with a neurodegenerative disorder such as Alzheimer’s disease, it has been proposed that the age-related inefficiency of CMA is accelerated. This leads to toxic aggregations, or clumps, of damaged proteins that upset the balance of proteins in the brain and entrap functional proteins, generating more blockage. Without CMA, our cell’s cleanup mechanism, this cellular landfill continues to build and begins to interfere with other critical biological processes.
In April 2021, Dr. Ana Maria Cuervo and her team of researchers at the Albert Einstein College of Medicine published a breakthrough study that investigated the relationship between inefficient CMA and the progression of neurodegenerative diseases in a mouse model of Alzheimer’s disease [3]. Cuervo, the co-study leader and co-director of the Institute for Aging Research at Einstein, noted that “these [mice], similar to the [Alzheimer’s] patients, have decreased memory, develop depression and [have] lack of engagement in general.” Using these mouse models, the first step of the study was to confirm that CMA does, in fact, have an impact on the balance of proteins in the brain. To investigate this, researchers generated a CMA-deficient mouse model through knockout, or removal, of the gene that encodes CMA. When compared against the mice with normal CMA levels, the CMA-deficient mice exhibited characteristics that align with rodent models of Alzheimer’s disease. These characteristics included reduced short-term memory, abnormal motor skills, and other dysfunctional behaviors. By interfering with the cells’ ability to regulate proteins, this finding proves that the proper balance of proteins in the brain contributes to the maintenance of stable neurological function.
The link between CMA deficiency and abnormal neurological symptoms may also be reversed, further emphasizing the importance of CMA in the brain. In a second experiment, researchers examined whether they could observe deficient CMA in mice that were already diagnosed with early Alzheimer’s disease. The results revealed lower levels of CMA activity in the mice that were afflicted with early Alzheimer’s disease. Ultimately, these findings indicated that in the early stages of Alzheimer’s disease, CMA activity is decreased and is likely contributing to the harm caused by aggregated proteins.
With a more concrete understanding of how CMA plays a role in neurological disorders, Cuervo and her team of researchers created a drug that could be used to treat the CMA-related symptoms observed in Alzheimer’s disease. Her vision for this new drug was that “if [we] could increase the removal of these proteins or the cleaning process that occurs normally inside the brain, it might be enough to eliminate toxic proteins.” This pharmaceutical re-energizes a component of the CMA apparatus, allowing a more efficient clearing of protein debris that may otherwise create blockages and eventually manifest in neurological symptoms. In a typical Alzheimer’s patient, “the sheer amount of defective protein overwhelms CMA and essentially cripples it,” Cuervo continues. Essentially, since the levels of faulty protein are markedly higher in Alzheimer’s patients, the CMA process must be functioning optimally. This new drug, CA, acts as a CMA enhancer by interacting with a
receptor, a type of cellular gatekeeper. In a healthy individual, chaperones, or cellular “helpers,” lock onto faulty proteins and guide them to a specific compartment within the cell, the lysosome. A single cell can have hundreds of lysosomes, each of which is tightly sealed from the rest of the cell due to its highly acidic contents. Once the chaperone, faulty protein in hand, has reached the lysosome, it docks to the compartment and releases the protein into the lysosome to be digested. The entry of the faulty proteins into the lysosome is monitored by various cellular gatekeepers present on the surface of the lysosome, one of which is the LAMP2A receptor. Throughout one’s life, the production of the LAMP2A receptor is constant. However, with age, the deterioration of LAMP2A receptors is accelerated. CA specifically targets this challenge by “[restoring] LAMP2A to youthful levels, enabling CMA to get rid of defective proteins so they can’t form those toxic protein clumps” as explained by Cuervo. By increasing the number of LAMP2A receptors, or gates, on the lysosomal surface, researchers were able to increase the channeling of faulty proteins into the lysosome which acts as the garbage disposal of the cell.
This new treatment, despite still being in its early stages of testing, provides an optimistic glance at potentially revolutionizing treatment for those suffering from neurological disorders that are caused by protein aggregation. Although it may be a while before Alzheimer’s patients are free from the daily burden of reorganizing their mental file cabinets, this study sheds light on a previously underscored cellular process and reveals a new avenue for Alzheimer’s research to explore. As Dr. Cuervo concludes, “this [finding] can be considered as an important step forward, or as a very good proof that enhancing cellular cleaning can be a way to develop therapeutics or interventions that can cure Alzheimer’s disease.”
References
- Armstrong RA (2013). What causes alzheimer’s disease?. Folia neuropathologica, 51(3), 169–188. https://doi.org/10.5114/fn.2013.37702
- Bejarano E & Cuervo, AM (2010). Chaperone-mediated autophagy. Proceedings of the American Thoracic Society, 7(1), 29–39. https://doi.org/10.1513/pats.200909-102JS
Bourdenx M, Martín-Segura A, Scrivo A, Rodriguez-Navarro JA, Kaushik S, Tasset I, Diaz A, Storm NJ, Xin Q, Juste YR, Stevenson E, Luengo E, Clement CC, Choi SJ, Krogan NJ, Mosharov EV, Santambrogio L, Grueninger F, Collin L, Swaney DL, Cuervo, AM. (2021). Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, 184(10), 2696–2714.e25. https://doi.org/10.1016/j.cell.2021.03.048
Factors Involved in the Development of Alzheimer’s Disease
By Nicole Strossman, Biochemistry & Molecular Biology, ‘17
Author’s Note:
“I chose to write this review for my UWP 104F after reading about potential treatments for Alzheimer’s Disease. As this is a disease that affects such a wide variety of people, and currently has no cure, I wanted to educate myself about the developments regarding it. Although the potential treatments are still under investigation, they provide hope for people affected by a currently incurable disease.”
New Target For Alzheimer’s Treatment
By David Ivanov, Biochemistry and Molecular Biology, ’15
A group of researchers studying brain cells have found a new potential target for pharmacological therapies that may help treat Alzheimer’s disease. Beta amyloid plaque, which appears to be a toxic build up of fragments of amyloid precursor protein (APP) in the brain, has long been associated with Alzheimer’s disease, and has been one of the major targets for Alzheimer’s treatment. Amyloid precursor protein plays an important role in the brain, and when this protein is broken down in nerve cells the toxic byproduct beta amyloid is formed. (more…)