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Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although the causes of damage have been proposed in every olfactory system including olfactory epithelium, olfactory bulb and olfactory cortex, the main causes of AD- related hyposmia are largely unknown.
Methods: We here focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also histologically confirmed the pathological changes in three-month-old 5xFAD mouse models which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of anatomical plane.
Results: We observed the odorant group, which 5xFAD mouse could not detect, also neither did physiologically activate the OSNs that propagate to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the ecto-ventrally located OSNs that showed reduced responses to odorants. We also observed irreversible damage to the ecto-region of the olfactory epithelium by measuring impaired neuronal turnover ratio from the basal cells to the matured OSNs.
Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely-associated with peripheral OSN’s loss could be a leading cause of the AD-related hyposmia, a characteristic of early AD.
Keywords
Alzheimer’s disease, Olfactory dysfunction, β-amyloid, 5xFAD, Olfactory sensory neuron, Endodorsal/Ectoventral position, Odor detection test, Ca2+ imaging, Topographic analysis, Neuronal turnover
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CURRENT STATUS: Published
View the published article at Alzheimer's Research & Therapy.
No community comments so far
Editorial decision: Accept
On 19 Nov, 2020
Editor assigned
On 18 Nov, 2020
Submission checks complete
On 18 Nov, 2020
Editor invited
On 18 Nov, 2020
No comments provided
Review #3 received
Received 14 Nov, 2020
Review #2 received
Received 10 Nov, 2020
Reviewer #3 agreed
On 06 Nov, 2020
Reviewer #2 agreed
On 06 Nov, 2020
Editor assigned
On 03 Nov, 2020
Reviewers invited
Invitations sent on 03 Nov, 2020
Reviewer #1 agreed
On 03 Nov, 2020
Review #1 received
Received 03 Nov, 2020
Submission checks complete
On 03 Nov, 2020
Editor invited
On 03 Nov, 2020
Version 1
Posted 07 Aug, 2020
No comments provided
Review #3 received
Received 14 Sep, 2020
Editorial decision: Major Revision
On 14 Sep, 2020
Review #2 received
Received 13 Sep, 2020
Reviewer #3 agreed
On 31 Aug, 2020
Reviewer #2 agreed
On 28 Aug, 2020
Review #1 received
Received 21 Aug, 2020
Reviewer #1 agreed
On 11 Aug, 2020
Reviewers invited
Invitations sent on 10 Aug, 2020
Submission checks complete
On 06 Aug, 2020
Editor assigned
On 06 Aug, 2020
First submitted
On 05 Aug, 2020
Editor invited
On 05 Aug, 2020
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Subject Areas
Cognitive Neuroscience
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See the published version of this preprint at Alzheimer's Research & Therapy.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Alzheimer's Research & Therapy.
No community comments so far
Editorial decision: Accept
On 19 Nov, 2020
Editor assigned
On 18 Nov, 2020
Submission checks complete
On 18 Nov, 2020
Editor invited
On 18 Nov, 2020
No comments provided
Review #3 received
Received 14 Nov, 2020
Review #2 received
Received 10 Nov, 2020
Reviewer #3 agreed
On 06 Nov, 2020
Reviewer #2 agreed
On 06 Nov, 2020
Editor assigned
On 03 Nov, 2020
Reviewers invited
Invitations sent on 03 Nov, 2020
Reviewer #1 agreed
On 03 Nov, 2020
Review #1 received
Received 03 Nov, 2020
Submission checks complete
On 03 Nov, 2020
Editor invited
On 03 Nov, 2020
Version 1
Posted 07 Aug, 2020
No comments provided
Review #3 received
Received 14 Sep, 2020
Editorial decision: Major Revision
On 14 Sep, 2020
Review #2 received
Received 13 Sep, 2020
Reviewer #3 agreed
On 31 Aug, 2020
Reviewer #2 agreed
On 28 Aug, 2020
Review #1 received
Received 21 Aug, 2020
Reviewer #1 agreed
On 11 Aug, 2020
Reviewers invited
Invitations sent on 10 Aug, 2020
Submission checks complete
On 06 Aug, 2020
Editor assigned
On 06 Aug, 2020
First submitted
On 05 Aug, 2020
Editor invited
On 05 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Alzheimer's Research & Therapy.
Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although the causes of damage have been proposed in every olfactory system including olfactory epithelium, olfactory bulb and olfactory cortex, the main causes of AD- related hyposmia are largely unknown.
Methods: We here focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also histologically confirmed the pathological changes in three-month-old 5xFAD mouse models which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of anatomical plane.
Results: We observed the odorant group, which 5xFAD mouse could not detect, also neither did physiologically activate the OSNs that propagate to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the ecto-ventrally located OSNs that showed reduced responses to odorants. We also observed irreversible damage to the ecto-region of the olfactory epithelium by measuring impaired neuronal turnover ratio from the basal cells to the matured OSNs.
Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely-associated with peripheral OSN’s loss could be a leading cause of the AD-related hyposmia, a characteristic of early AD.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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