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academies
13
th
International Conference on
Alzheimers Disease and Dementia
November 25-26, 2019 | Frankfurt, Germany
Journal of Psychology and Cognition | Volume: 04
J Psychol Cognition, Volume: 04
Role of HIF-1α/lncRNA BACE1-AS axis in HIV-1 Tat-mediated astrocytic amyloidogenesis:
Implications of Alzheimer’s like pathology in HIV
Shilpa Buch
University of Nebraska Medical Center, USA
I
ncreased life expectancy of HIV+ patients in the
current era of effective treatment is unfortunately
accompanied with the continued prevalence of HIV-
associated neurological disorders & risk of age-associated
comorbidities such as Alzheimer’s Disease (AD). In the
current study we sought to assess the contribution of non-
neuronal cells such as the astrocytes in HIV-Tat-mediated
amyloidogenesis. Findings in SIV-infected macaques/ HIV+
subjects with differential cognitive status demonstrated
brain region specific upregulation of the amyloid precursor
protein (APP), Aβ1-42 & Aβ 1-40, in astrocytes. Along
these lines, in the in vitro studies involving human primary
astrocytes (HPA) exposed to HIV protein That there was
increased expression of AD markers such as β-site cleaving
enzyme (BACE1) enzyme, APP, Aβ 1-42 & Aβ 1-40. These
findings were also validated by increased expression
of cellular BACE-1 activity & Aβ-42 in the supernatant
fluids of Tat-exposed astrocytes. Molecular mechanism(s)
involved upregulation of the hypoxia inducible factor
(HIF-1α), its translocation & binding to the lncRNA
BACE-1AS in the nucleus, resulting in the formation of
the BACE-1AS/BACE1 RNA complex, which increased
the expression of BACE-1 involving transcriptional, post
transcriptional & translational mechanisms, as well as
increased activity, leading, in turn, to generation of Aβ-
42 protein via cleavage of APP. Gene silencing approaches
confirmed the regulatory role of HIF-1α in BACE-1AS/
BACE-1 in Tat-mediated amyloidogenesis. This is the first
report implicating the role of HIF-1α-lncRNA BACE1-AS
in Tat-mediated induction of astrocytic amyloidogenesis.
Strategies aimed at targeting the HIF-1α-lncRNA BACE1-AS
complex could be developed as adjunctive therapies for
HAND-associated comorbidity of AD.
Biography
Shilpa Buch, Phd is currently a Professor & Vice Chair for Research and
the Director of the Nebraska Center for Substance Abuse research at the
University of Nebraska. She received my PhD in 1982 in Microbiology
from Maharaja Sayajirao University in Baroda, India and moved to
Canada for postdoctoral training. She began her independent research
career as an Assistant Professor at the Hospital for Sick Kids, Toronto,
following which, she moved to Kansas University and embarked on
a research area focused on understanding how addictive drugs co-
operate with HIV-1 to exacerbate neurological complications. she
rose through the ranks at Kansas and in 2007, made a move as a full
Professor to University of Nebraska in Omaha. Research approaches
used in my lab involve a multipronged approach comprising of a
variety of complementary model systems ranging from cell cultures
to rodent models to the higher more relevant macaque model of SIV
pathogenesis. More recently, her research interest is centered on
exploring how exosomes act as conduits to transport key signaling
mediators (small noncoding RNAs/microRNAs) to distant recipient cells
as a means to regulate gene expression and cellular cross talk. She lead
an active research program involving collaborations both nationally and
internationally, with over 160 peer-reviewed publications. She have
consistently held NIH funding throughout my career and continue to
serve on NIH study sections.
e:
sbuch@unmc.edu