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J Pharmacol Ther Res 2017 Volume 1 Issue 2
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
Strategies for pathology-activated generation of reelin trafficking modulators for altering late-onset
Alzheimer’s disease progression
Ronald A Hill
and
Amal K Kaddoumi
University of Louisiana, USA
C
ompelling evidence continues to accrue that late-onset
(non-familial) Alzheimer’s disease (LOAD), arising early
in olfactory structures of the brain, progresses in a spatio-
temporally consistent pattern via propogating “inflammaging”
processes; predisposing susceptibility may be established
as early as gestationally. Genome-wide association studies
(GWASs) of cognitively uncompromised individuals who exhibit
apparent high pathology suggest that select combinations of
genetic attributes can confer resistance to cognitive decline;
and, although certain specifics of pathological signatures
differ from those in cognitively deteriorating individuals,
these might reflect successful defense against an otherwise
pathological chain of events. A central player emerging from
these GWASs is reelin, a large glycoprotein component of the
extracellular matrix (ECM). Though historically regarded mostly
as a key player in embryo-fetal development reelin exhibits
functional interplay in the adult brain with other molecular
constituents having clearly established associations with
LOAD, such as apolipoprotein E, and with the responsiveness
states of inflammaging-associated cells, notably microglia. The
complexities and relative paucity of knowledge regarding ECM
maintenance, remodeling, and functional dynamics, and the
analytical challenges involved in achieving increased clarity,
means that gaining therapeutically actionable traction will be
difficult; however, the tantalizing thought that GWASs of these
individuals may be showing us ways forward motivates rising to
these challenges. Reelin possessesmultiple functional domains,
and certain reelin fragments exhibit trafficking and function
disparate from intact glycoprotein. Very recently, ADAMTS-3
was identified as the catalyst of a proteolytic cleavage of reelin
shown to be inactivating in terms of reelin’s canonical activities.
Because of reelin remains heavily involved during adulthood
in dynamic brain maintenance and remodeling, deleterious
consequences can be expected from anatomically untargeted
alterations in reelin function. Potential strategies for pathology-
activated, localized generation of suitable modulators will thus
beneeded, andprogresswith respect todevising such strategies
will be shared in this presentation.
Speaker Biography
Ronald A Hill is now spanning almost 35 years, over a pharmaceutical sciences career.
He has aimed to become a generalist with high-level acumen in relating the Chemistry
of biologically active molecules to their interactions with, and actions on, humans
and their hosted organisms (normal microbiome, microbial pathogens, parasites).
The central focus of his own research has always related to the CNS, guided also by
the aim of constantly gaining acumen in molecular therapeutics design, molecular
biopharmaceutics, and molecular toxicology and in general, the science of successfully
bridging discovery at its earliest stages to clinical application. His educating duties at
the PhD and PharmD levels are extensive, and carried out with the underlying hope
that the molecular science and molecular design will be intelligently and artfully acted
on in clinical practice. His current research collaborations center on neurodegenerative
conditions and cancer.
e:
rhill@ulm.edu