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An overview on therapeutics attenuating amyloid ? level in Alzheimer s disease:
targeting neurotransmission, inflammation, oxidative stress and enhanced
cholesterol levels
#MMPMID27158324
Zhou X
; Li Y
; Shi X
; Ma C
Am J Transl Res
2016[]; 8
(2
): 246-69
PMID27158324
show ga
Alzheimer's disease (AD) is the most common underlying cause of dementia, and
novel drugs for its treatment are needed. Of the different theories explaining
the development and progression of AD, "amyloid hypothesis" is the most supported
by experimental data. This hypothesis states that the cleavage of amyloid
precursor protein (APP) leads to the formation of amyloid beta (A?) peptides that
congregate with formation and deposition of A? plaques in the frontal cortex and
hippocampus. Risk factors including neurotransmitter modulation, chronic
inflammation, metal-induced oxidative stress and elevated cholesterol levels are
key contributors to the disease progress. Current therapeutic strategies abating
AD progression are primarily based on anti-acetylcholinesterase (AChE) inhibitors
as cognitive enhancers. The AChE inhibitor, donepezil, is proven to strengthen
cognitive functions and appears effective in treating moderate to severe AD
patients. N-Methyl-D-aspartate receptor antagonist, memantine, is also useful,
and its combination with donepezil demonstrated a strong stabilizing effect in
clinical studies on AD. Nonsteroidal anti-inflammatory drugs delayed the onset
and progression of AD and attenuated cognitive dysfunction. Based upon
epidemiological evidence and animal studies, antioxidants emerged as potential AD
preventive agents; however, clinical trials revealed inconsistencies.
Pharmacokinetic and pharmacodynamic profiling demonstrated pleiotropic functions
of the hypolipidemic class of drugs, statins, potentially contributing towards
the prevention of AD. In addition, targeting the APP processing pathways,
stimulating neuroprotective signaling mechanisms, using the amyloid
anti-aggregants and A? immunotherapy surfaced as well-tested strategies in
reducing the AD-like pathology. Overall, this review covers mechanism of inducing
the A? formation, key risk factors and major therapeutics prevalent in the AD
treatment nowadays. It also delineates the need for novel screening approaches
towards identifying drugs that may prevent or at least limit the progression of
this devastating disease.
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