Icariin Ameliorates Alzheimer’s Disease Pathology by Alleviating Myelin Injury in 3 × Tg-AD Mice

Huang, Yu; Shi, Jing; Lin, Yiyou; Zhang, Shaodong; Luo, Qihang; Huang, Shengfu; Wang, Sichen; Wei, Jiale; Huang, Junhao; Li, Changyu; Ji, Liting

doi:10.1007/s11064-021-03507-7

Cited by 16 publications

(11 citation statements)

References 50 publications

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“…Recent studies have shown that treating myelin damage can reduce amyloid deposition and restore cognition. [62][63][64] As such, the second implication of these findings is that underexplored targets for treatment development and disease monitoring should be pursued at the very earliest stages of AD. For instance, selectively modulating innate immunity 65 to support myelin repair may be beneficial at the preclinical stage prior to neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, rather than a linear cascade of events, AD may be better conceptualized as synergistic, recursive, and critically, intimately tied to age‐related homeostatic changes such as myelin remodeling/repair. Recent studies have shown that treating myelin damage can reduce amyloid deposition and restore cognition 62–64 . As such, the second implication of these findings is that underexplored targets for treatment development and disease monitoring should be pursued at the very earliest stages of AD.…”

Section: Discussionmentioning

confidence: 99%

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Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease

Benitez

Jensen

Thorn

et al. 2022

Annals of Neurology

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Objective: The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease. Methods: Cognitively unimpaired participants ages 45 to 85 years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta-amyloid-negative (ABÀ) and -positive (AB+) participants differed on DKIbased conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra-axonal radial diffusivity [D e,⊥ ]) metrics, and whether these metrics were associated with other biomarkers. Results: We found significantly greater diffusion restriction (higher FA/AWF, lower MD/D e,⊥ ) in white matter in AB+ than ABÀ (partial η 2 =0.08-0.19), more notably in the extra-axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas D e,⊥ (a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume. Interpretation: These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease

Benitez

Jensen

Thorn

et al. 2022

Annals of Neurology

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“…The same LINGO-1 antibody decreased the myelin injury and improved memory deficits (Wu et al, 2018). A flavenol antioxidant improved memory in 3 × Tg-AD mice, which correlated with fewer amyloid plaques, increased myelin-related gene expression and decreased myelin damage (Yu et al, 2022).…”

Section: Reversing White Matter Injury Improves Cognition In Animal A...mentioning

confidence: 94%

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Sharp

DeCarli

Jin

et al. 2023

Front. Aging Neurosci.

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We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

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“…Myelin basic protein (Mbp) is a marker for myelin damage. In 3 × Tg-AD mouse model, icariin treatment improved the learning and memory, reduced Aβ deposition and tau protein phosphorylation in the hippocampus, while increased myelin-related gene expression including Mbp with reduced myelin damage [43]. Mbp was reduced -6.1-fold, while no change was observed after DNLA.…”

Section: Downregulated Protein/genes In Aged Samp8 Mice and Effects O...mentioning

confidence: 92%

Proteomic Analysis of Anti-Aging Effects of <em>Dendrobium Nobile Lindl.</em> Alkaloids in Aging-Accelerated SAMP8 Alzheimer’s Mice

Liu¹,

Lv²,

Liu³

et al. 2022

Preprint

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Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit cognitive defects and neuron loss with aging, and are used to study anti-aging effects of Dendrobium nobile alkaloids (DNLA). SAMP8 mice were orally given DNLA from ages 6 to 10 months. At 10 months of age, behavioral tests and neuron damage were evaluated. Protein was extracted and subjected to phosphorylated proteomic analysis. The cognitive deficits and neuron loss in hippocampus and cortex of aged SAMP8 mice were improved by DNLA. Hippocampal proteomic analysis showed differentially expressed protein/genes in SAMP8 compared to age-matched senescence-accelerated resistant mice, including altered tubulin binding, microtubule binding, etc. via Gene Oncology. KEGG revealed endocytosis, mRNA surveillance, tight junction, protein processing in endoplasmic reticulum, aldosterone synthesis and secretion, and glucagon signaling pathway changes. Upregulated protein/genes in the hippocampus of SAMP8 mice, such as Lmtk3, Usp10, Dzip1, Csnk2b, and Rtn1, were attenuated by DNLA; whereas downregulated protein/genes, such as Kctd16, Psd3, Bsn, Atxn2l, and Kif1a, were rescued by DNLA. The aberrant protein/gene expressions of SAMP8 mice were correlated with transcriptome changes of Alzheimer’s disease in the GEO database, and were attenuated by DNLA. Thus, DNLA improved cognitive dysfunction and ameliorated neuronal injury in aged SAMP8 mice, and attenuated aberrant protein/gene expressions.

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Icariin Ameliorates Alzheimer’s Disease Pathology by Alleviating Myelin Injury in 3 × Tg-AD Mice

Cited by 16 publications

References 50 publications

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Proteomic Analysis of Anti-Aging Effects of <em>Dendrobium Nobile Lindl.</em> Alkaloids in Aging-Accelerated SAMP8 Alzheimer’s Mice

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