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Cited by 105Alzheimer's disease research and treatmentsHearing, Cochlea, Tinnitus, GeneticsMitochondrial Function and Pathology

The DOI matches its Crossref record; 123 of the 123 references it cites were found in a registry or an index.

Cognitive Decline, Dementia, Alzheimer’s Disease and Presbycusis: Examination of the Possible Molecular Mechanism

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Shen, Yilin, Ye, Bin, Chen, Penghui, Wang, Quan, Fan, Cui, Shu, Yilai, Xiang, Mingliang·2018·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.00394PMC PMC6002513
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Abstract

The incidences of presbycusis and dementia are high among geriatric diseases. Presbycusis is the general term applied to age-related hearing loss and can be caused by many risk factors, such as noise exposure, smoking, medication, hypertension, family history, and other factors. Mutation of mitochondrial DNA in hair cells, spiral ganglion cells, and stria vascularis cells of the cochlea is the basic mechanism of presbycusis. Dementia is a clinical syndrome that includes the decline of cognitive and conscious states and is caused by many neurodegenerative diseases, of which Alzheimer's disease (AD) is the most common. The amyloid cascade hypothesis and tau hypothesis are the two major hypotheses that describe the AD pathogenic mechanism. Recent studies have shown that deposition of Aβ and hyperphosphorylation of the tau protein may cause mitochondrial dysfunction. An increasing number of papers have reported that, on one hand, the auditory system function in AD patients is damaged as their cognitive ability declines and that, on the other hand, hearing loss may be a risk factor for dementia and AD. However, the relationship between presbycusis and AD is still unknown. By reviewing the relevant literature, we found that the SIRT1-PGC1α pathway and LKB1 (or CaMKKβ)-AMPK pathway may play a role in the preservation of cerebral neuron function by taking part in the regulation of mitochondrial function. Then vascular endothelial growth factor signal pathway is activated to promote vascular angiogenesis and maintenance of the blood-brain barrier integrity. Recently, experiments have also shown that their expression levels are altered in both presbycusis and AD mouse models. Therefore, we propose that exploring the specific molecular link between presbycusis and AD may provide new ideas for their prevention and treatment.

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Crossref · 10.3389/fnins.2018.00394

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Figures

FIGURE 1 Auditory signal pathway and possible insults to the auditory nervous system caused by Alzheimer’s disease. The auditory nervous pathway originates from spiral ganglion cells in cochlea. Then, the axons of spiral ganglion cells project to the cochlear nucleus complex. Next, most of the axons from the cochlear nucleus complex cross the midline and ascend in the contralateral lateral lemniscus, terminating in the inferior colliculus and medial geniculate body. Another part of axons project to the superior olivary nucleus and then terminate in the inferior colliculus and medial geniculate body. Finally, all ascending neurons form an auditory radiation and terminate in the auditory center of the transverse temporal gyrus. Every link in the auditory pathway may display pathological changes associated with AD, thus leading to hearing impairment.
FIGURE 1 Auditory signal pathway and possible insults to the auditory nervous system caused by Alzheimer’s disease. The auditory nervous pathway originates from spiral ganglion cells in cochlea. Then, the axons of spiral ganglion cells project to the cochlear nucleus complex. Next, most of the axons from the cochlear nucleus complex cross the midline and ascend in the contralateral lateral lemniscus, terminating in the inferior colliculus and medial geniculate body. Another part of axons project to the superior olivary nucleus and then terminate in the inferior colliculus and medial geniculate body. Finally, all ascending neurons form an auditory radiation and terminate in the auditory center of the transverse temporal gyrus. Every link in the auditory pathway may display pathological changes associated with AD, thus leading to hearing impairment.CC BY · PubMed Central
FIGURE 2 Reactive oxygen species (ROS)/VEGF pathway. Aging often causes reduced ROS clearance and increased ROS activity. Accumulation of ROS in cells can cause mtDNA mutations and mitochondrial dysfunction and then result in decreased levels of VEGF. Decreased levels of VEGF may lead to Aβ deposition and hamper the repair of hair cells and spiral ganglions in the inner ear as well as the reconstruction of blood vessels in the brain, resulting in dementia or presbycusis. Further studies are still needed to determine whether there is a time order of the occurrence of both diseases and whether hearing loss caused by a decrease of VEGF will further increase the risk of dementia and its progression.
FIGURE 2 Reactive oxygen species (ROS)/VEGF pathway. Aging often causes reduced ROS clearance and increased ROS activity. Accumulation of ROS in cells can cause mtDNA mutations and mitochondrial dysfunction and then result in decreased levels of VEGF. Decreased levels of VEGF may lead to Aβ deposition and hamper the repair of hair cells and spiral ganglions in the inner ear as well as the reconstruction of blood vessels in the brain, resulting in dementia or presbycusis. Further studies are still needed to determine whether there is a time order of the occurrence of both diseases and whether hearing loss caused by a decrease of VEGF will further increase the risk of dementia and its progression.CC BY · PubMed Central
FIGURE 3 SIRTl/PGC-1α (FNDC5) pathway. Reduced expression of SIRT1- PGC-1α caused by many factors may impair the synthesis and respiratory function of mitochondria, thereby causing neuronal degeneration and cell apoptosis, thus leading to presbycusis. At the same time, reduced expression of SIRT1- PGC-lα in the brain can cause increased production of Aβ and reduced production of BDNF and thus contribute to the incidence of dementia. Therefore, SIRT1/PGC-lα (FNDC5) may be a possible drug target to prevent patients with ARHL from developing AD.
FIGURE 3 SIRTl/PGC-1α (FNDC5) pathway. Reduced expression of SIRT1- PGC-1α caused by many factors may impair the synthesis and respiratory function of mitochondria, thereby causing neuronal degeneration and cell apoptosis, thus leading to presbycusis. At the same time, reduced expression of SIRT1- PGC-lα in the brain can cause increased production of Aβ and reduced production of BDNF and thus contribute to the incidence of dementia. Therefore, SIRT1/PGC-lα (FNDC5) may be a possible drug target to prevent patients with ARHL from developing AD.CC BY · PubMed Central
FIGURE 4 Liver kinase B1 (LKB1) and CaMKKβ/AMPK pathway. Decreased activity of AMPK will lead to abnormalities in mitochondrial synthesis and normal functions, such as oxidative respiration, as well as alterations of autophagy, which render cells unable to handle changes in the microenvironment. Decreased activity of AMPK will also cause less degradation of Aβ and more phosphorylation of tau. LKB1 and CaMKKβ are required for the activation of AMPK and are important for the stability of stereocilia in hair cells and protection of auditory cortex neurons, respectively. Although there is currently no evidence showing that LKB1 and CaMKKβ change in the ear or brain due to aging, the environment, diet or other factors, we speculate that if expression of LKB 1 and CaMKKβ is altered by the above factors, they would not only cause hearing loss but also affect downstream phosphorylation of AMPK, leading to AD. However, the activation of AMPK may exert a dual influence, which may have an opposite effect on cell death and survival.
FIGURE 4 Liver kinase B1 (LKB1) and CaMKKβ/AMPK pathway. Decreased activity of AMPK will lead to abnormalities in mitochondrial synthesis and normal functions, such as oxidative respiration, as well as alterations of autophagy, which render cells unable to handle changes in the microenvironment. Decreased activity of AMPK will also cause less degradation of Aβ and more phosphorylation of tau. LKB1 and CaMKKβ are required for the activation of AMPK and are important for the stability of stereocilia in hair cells and protection of auditory cortex neurons, respectively. Although there is currently no evidence showing that LKB1 and CaMKKβ change in the ear or brain due to aging, the environment, diet or other factors, we speculate that if expression of LKB 1 and CaMKKβ is altered by the above factors, they would not only cause hearing loss but also affect downstream phosphorylation of AMPK, leading to AD. However, the activation of AMPK may exert a dual influence, which may have an opposite effect on cell death and survival.CC BY · PubMed Central

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Research works printed but not linked: 5

  1. de Carvalho, 2015, World Report on aging and Health.
  2. Lonsbury-Martin, 2009, “Physiology of the auditory and vestibular systems,” in, The Ballenger’s Otolaryngology: Head and Neck Surgery, 45
  3. Mathers, 2005, Updated Projections of Global Mortality and Burden of Disease, 2002-2030: Data Sources, Methods and Results.
  4. Mills, 2009, “Presbyacusis and presbyastasis,” in, the Ballenger’s Otolaryngology: Head and Neck Surgery, 333
  5. 2017, Deafness and Hearing Loss.

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Metadata

Authors
Shen, Y., Ye, B., Chen, P., Wang, Q., Fan, C., Shu, Y., & Xiang, M.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Fudan University (CN)
Corresponding author
  • Shu, Yilai
  • Xiang, Mingliang
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2018-06-08
Volume
12
Pages
394-394
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.00394
PMC
PMC6002513
OpenAlex
W2805491381
Cited by
105
References
122
Citations by year
2026: 10 · 2025: 8 · 2024: 6 · 2023: 16 · 2022: 13 · 2021: 21 · 2020: 10 · 2019: 19 · 2018: 2
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81670926, 81271088, 14DZ2260300)
  • Science and Technology Commission of Shanghai Municipality (14DZ2260300, 15411950303)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
age-related hearing loss, Alzheimer's disease, dementia, cognitive decline, mitochondrial dysfunction, mitochondrial DNA mutations, amyloid hypothesis, tau hyperphosphorylation, LKB1/AMPK pathway, vascular endothelial growth factor, blood-brain barrier

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