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Volume 8 Journal of Alzheimers Disease & Parkinsonism
ISSN: 2161-0460 Euro Dementia 2018
May 24-25, 2018
May 24-25, 2018 | Vienna, Austria
11th International Conference on
Alzheimers Disease & Dementia
Targeting hypoxic signals as a therapeutic approach to Alzheimer’s disease
Mario Durán-Prado1, Javier Frontiñán-Rubio1, Francisco Javier Sancho-Bielsa1, Cristina Pedrero-Prieto1, Juan Ramón Peinado 1, Lidia Giménez-Llort2 and
Francisco Javier Alcaín1
1University of Castilla-La Mancha, Spain
2Autonomous University of Barcelona, Spain
Hypoxia, “hypoxic signals” as increased mitochondrial radical oxygen species levels and hypoperfusion occurs early in
Alzheimer`s disease, inducing white matter lesions and correlating with dementia. Indeed, these abnormalities turn
towards a cerebral microvascular pathology which accompanies age-related cognitive dysfunction and neurodegeneration.
Therefore, alleviating cerebral microvascular pathology through the blockade of early hypoxic signals becomes a promising
strategy to slow down Alzheimer`s progression. We have described that hypoxic signals (as oxidative stress) in early stages
preceding vascular damage, beta amyloid deposition and appearance of brain parenchymal hypoxia, are premorbid and
prodromal indicators of Alzheimer`s in the 3xTg-ADmurine model of the disease. Moreover, circulating beta amyloid peptide
damages the cerebral microvasculature through mechanisms that involve an increase in hypoxic signals, specifically in the
mitochondrial compartment of endothelial cells, as it is an increase in superoxide ion, driving to endothelial cell death and
therefore, to a compromise of cerebral microvessels function. Our results obtained with endothelial cells cultures, exposed to
beta amyloid peptide, in vitro, clearly indicate that hypoxic cell responses can be blocked using a mitochondrial protector as
coenzyme Q10, a lipophilic antioxidant involved in electrons transport from the mitochondrial complex I to complexes II and
III, which results in a protective effect against beta amyloid cell toxicity through raising the whole cell metabolic status. We
have recently assayed the effect of targeting mitochondrial hypoxic signals, in vivo, in 3xTg-AD mice. Animals were fed from
prodromal stages of the disease with ubiquinol (the reduced form of coenzyme Q10) diet, compared to vehicle diet and wild
type mice. Firstly, hippocampal chronic inflammation and peripheral leukocytes-oxidative stress found in 3xTg-ADmice were
reversed by ubiquinol, which was mirrored by a reversion of the mice neuropathological status. Brain parenchyma hypoxia,
exacerbated in vehicle-fed 3xTg-AD mice also in colocalization with large and abundant beta amyloid plaques, disappeared
upon intervention with ubiquinol as well as the amount and size of beta amyloid plaques. This is correlated with a reduction
in collagen deposition in the basal lamina of brain microvessels, a clear indicator of an improved brain microvessels function.
Altogether, our results indicate that combating hypoxic signals from early prodromal Alzheimer´s stages could be a successful
strategy to improve microvessels function, reducing parenchymal hypoxia, accumulation of beta amyloid plaques and, maybe,
improving the delivery of memantine.
Recent Publications
1. Frontiñán-Rubio, Javier, Sancho-Bielsa, Francisco Javier, Peinado, Juan Ramón, LaFerla, Frank, Giménez-Llort, Lidia,
Durán-Prado, Mario and Alcain, Francisco Javier () Sex-dependent colocalization of hipoxia and beta-amyloid plaques
in hippocampus and enthorhinal cortex in 3xTg-ADmice is reversed by long-term treatment with ubiquinol and vitamin
C. In review (second) in Mol. Cell. Neurosci.
2. Durán-Prado Mario, Javier Frontiñán, Raquel Santiago-Mora, Juan Ramón Peinado, Cristina Parrado-Fernández, et al.
(2014) Coenzyme q10 protects human endothelial cells from β-amyloid uptake and oxidative stress-induced injury. PLoS
One 9(10): e109223.
3. Torres-Lista Virginia, Cristina Parrado-Fernández, Ismael Alvarez-Montón, Javier Frontiñán-Rubio, Mario Durán-
Prado, et al. (2014) Neophobia, NQO1 and SIRT1 as premorbid and prodromal indicators of AD in 3xTg-AD mice.
Behav. Brain Res. 271:140-6.
Mario Durán-Prado et al., J Alzheimers Dis Parkinsonism 2018, Volume 8
DOI:10.4172/2161-0460-C3-042