Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology

Bassil, Fares; Brown, Hannah J.; Pattabhiraman, Shankar; Iwasyk, Joe E.; Maghames, Chantal; Meymand, Emily S.; Cox, Timothy; Riddle, Dawn M.; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1016/j.neuron.2019.10.010

Cited by 145 publications

(135 citation statements)

References 72 publications

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“…The finding of defective neurogenesis in the brains of AD patients is consistent with experimental studies using animal models of AD, in which significantly lower levels of neurogenesis are seen in both the SVZ and hippocampus [14]. Reduced neurogenesis has been reported in several AD animal models, including 5xFAD and Tg2576 mice, and OXYS rats [15][16][17][18].…”

Section: Introductionsupporting

confidence: 82%

Intracranial alternating current stimulation facilitates neurogenesis in a mouse model of Alzheimer’s disease

et al. 2020

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Background: Neurogenesis is significantly impaired in the brains of both human patients and experimental animal models of Alzheimer's disease (AD). Although deep brain stimulation promotes neurogenesis, it is an invasive technique that may damage neural circuitry along the path of the electrode. To circumvent this problem, we assessed whether intracranial electrical stimulation to the brain affects neurogenesis in a mouse model of Alzheimer's disease (5xFAD). Methods and results: We used Ki67, Nestin, and doublecortin (DCX) as markers and determined that neurogenesis in both the subventricular zone (SVZ) and hippocampus were significantly reduced in the brains of 4-month-old 5xFAD mice. Guided by a finite element method (FEM) computer simulation to approximately estimate current and electric field in the mouse brain, electrodes were positioned on the skull that were likely to deliver stimulation to the SVZ and hippocampus. After a 4-week program of 40-Hz intracranial alternating current stimulation (iACS), neurogenesis indicated by expression of Ki67, Nestin, and DCX in both the SVZ and hippocampus were significantly increased compared to 5xFAD mice who received sham stimulation. The magnitude of neurogenesis was close to the wild-type (WT) age-matched unmanipulated controls. Conclusion: Our results suggest that iACS is a promising, less invasive technique capable of effectively stimulating the SVZ and hippocampus regions in the mouse brain. Importantly, iACS can significantly boost neurogenesis in the brain and offers a potential treatment for AD.

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Section: Introductionsupporting

confidence: 82%

Intracranial alternating current stimulation facilitates neurogenesis in a mouse model of Alzheimer’s disease

et al. 2020

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“…Aβ species are suggested as being pathological seeds and a spreading process of deteriorating proteinopathy in neurodegenerative disease (34). Indeed, a protein pathology like α-synuclein could be associated with the toxic aggregation of proteins by being associated with endogenous Aβ expression in 5xFAD mice (35), an α-synuclein measured together with Aβ expression in the olfactory epithelium of human APP-overexpressing transgenic mice (N5 TgCRND8) (36). Hence, Aβ present in OSNs not only can generate and accumulate misfolding protein itself but also is enough to establish systemic vulnerability in the early stage of AD.…”

Section: Discussionmentioning

confidence: 99%

Region specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice

Son

Yoo

Kang

et al. 2020

Preprint

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Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas. The pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically 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 the anatomical plane. Results: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the 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 AD-related hyposmia, a characteristic of early AD.

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“…PrP C reportedly binds four Cu atoms in the octarepeat domain (-PHGGGWGQ-) in its N-terminal. Cu can also bind to His 96 and His 111 [69]. Huang et al found that PrP C binds to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type and/or NMDA-type glutamate receptors and affects their function in a Cu-dependent manner [70].…”

Section: Prion Diseases and Neurometalsmentioning

confidence: 99%

“…α-Synuclein influences the processing of APP as well as AβP secretion [95]. Meanwhile, AβP promotes seeding and spreading α-synuclein [96]. It is also possible that PrP C affects the production of AβP by providing Cu to APP.…”

Section: Hypothesis: Loss Of Normal Regulatory Functions Of Amyloidogmentioning

confidence: 99%

Amyloids: Regulators of Metal Homeostasis in the Synapse

2020

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Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

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Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology

Cited by 145 publications

References 72 publications

Intracranial alternating current stimulation facilitates neurogenesis in a mouse model of Alzheimer’s disease

Intracranial alternating current stimulation facilitates neurogenesis in a mouse model of Alzheimer’s disease

Region specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice

Amyloids: Regulators of Metal Homeostasis in the Synapse

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