Retinoids as a Perspective in Treatment of Alzheimer’s Disease

Fahrenholz, Falk; Tippmann, Frank

doi:10.1159/000295662

Cited by 16 publications

(10 citation statements)

References 34 publications

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“…Alpha secretase activity results in cleavage of Ab preventing formation of the toxic forms of Ab 1-40 and Ab 1-42. Interestingly, these subtypes are highly expressed in the hippocampus and may modulate synaptic plasticity in adult animals [24,25]. These enzymes also act to stimulate the generation of a soluble neuroprotective fragment of APP, APP-s alpha [14,24].…”

Section: 1all-trans Retinoic Acidmentioning

confidence: 99%

“…Both RAR-a and RAR-b form heterodimers with RXR and can potentially stimulate the ADAM10 promoter. Interestingly, these subtypes are highly expressed in the hippocampus and may modulate synaptic plasticity in adult animals [24,25].…”

Section: 1all-trans Retinoic Acidmentioning

confidence: 99%

“…Acitretin upregulates ADAM10, which activates alphasecretase, shifting Ab metabolism away from amyloidigenic fragments formed by cleavage of the Ab peptide from APP by the action of beta-and gamma-secretase as discussed above 14,23,24,25 Acitretin is currently being investigated in AD in Germany (NCT01078168).…”

Section: Acitretinmentioning

confidence: 99%

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Retinoids for treatment of Alzheimer's disease

et al. 2012

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Retinoids are Vitamin A derivatives involved in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. Retinoids may also influence Amyloid beta processing upregulation of alpha secretase via ADAM10. Vitamin A and other retinoids also directly inhibit formation of Amyloid fibrils in vivo. These properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis. Retinoids are already used in treatment of acne vulgaris, psoriasis, neuroblastoma and acute promyelocytic leukemia. Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids. These studies need to address safety issues of retinoids in older populations, and hold hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness.

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Section: 1all-trans Retinoic Acidmentioning

confidence: 99%

Section: 1all-trans Retinoic Acidmentioning

confidence: 99%

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Retinoids for treatment of Alzheimer's disease

et al. 2012

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“…In line with this, overexpression of ADAM10 in vivo resulted in an inhibition of Aß production, most likely via increased levels of APPsα ([66]. ; reviewed in [63]). An increase in Adam10 mRNA as observed in our study could similarly affect BACE1 activity via increased APPsα levels, thereby shifting the balance of APP processing further towards the non-amyloidogenic pathway.…”

Section: Discussionmentioning

confidence: 83%

Upregulation of APP, ADAM10 and ADAM17 in the Denervated Mouse Dentate Gyrus

et al. 2014

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The disintegrin and metalloproteinases ADAM10 and ADAM17 are regarded as the most important α-secretases involved in the physiological processing of amyloid precursor protein (APP) in brain. Since it has been suggested that processing of APP by α-secretases could be involved in the reorganization of the brain following injury, we studied mRNA expression of the two α-secretases Adam10 and Adam17, the ß-secretase Bace1, and the App-gene family (App, Aplp1, Aplp2) in the dentate gyrus of the mouse following entorhinal denervation. Using laser microdissection, tissue was harvested from the outer molecular layer and the granule cell layer of the denervated dentate gyrus. Expression levels of candidate genes were assessed using Affymetrix GeneChip Mouse Gene 1.0 ST arrays and reverse transcription-quantitative PCR, revealing an upregulation of Adam10 mRNA and Adam17 mRNA in the denervated outer molecular layer and an upregulation of Adam10 mRNA and App mRNA in the dentate granule cell layer. Immunolabeling for ADAM10 or ADAM17 in combination with markers for astro- and microglia revealed an increased labeling of ADAM10 and ADAM17 in the denervated outer molecular layer that was associated with reactive astrocytes but not with microglia. Collectively, these data show that denervation affects the expression level of APP and its two most important α-secretases. This suggests that APP-processing could be shifted towards the non-amyloidogenic pathway in denervated areas of the brain and, thus, towards the formation of neuroprotective APP cleavage products, such as APPsα.

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“…After 12 d of RA treatment, the SY‐SY5Y cell line acquired a differentiated neuronal phenotype, with extensive neurites and branching, as evidenced by light microscopy and expression of specific neuronal markers (MAP2B, synaptophysin, and tyrosine hydroxylase; data not shown). RA‐induced differentiation of SH‐SY5Y cells is associated with significant increases in sAPPα levels in conditioned media of differentiated vs. undifferentiated cells (33–35); suggesting that differentiation shifts APP processing toward the nonamyloidogenic pathway (36, 37). In our study, induction of differentiation increased synaptopysin, APP, and sAPPα levels, as well as APP NTFs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel amyloid precursor protein processing pathway that generates secreted N‐terminal fragments

Vella

Cappai

2012

FASEB j.

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Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the β-amyloid (Aβ) peptide is a central event in AD. While the pathway that generates Aβ is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of α-secretase or β-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.

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Retinoids as a Perspective in Treatment of Alzheimer’s Disease

Cited by 16 publications

References 34 publications

Retinoids for treatment of Alzheimer's disease

Retinoids for treatment of Alzheimer's disease

Upregulation of APP, ADAM10 and ADAM17 in the Denervated Mouse Dentate Gyrus

Identification of a novel amyloid precursor protein processing pathway that generates secreted N‐terminal fragments

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