Enhancing autophagy in Alzheimer's disease through drug repositioning

https://doi.org/10.1016/j.pharmthera.2022.108171Get rights and content
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Abstract

Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is “drug repositioning” or “drug repurposing”. In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.

Keywords

Autophagy induction
mTOR inhibitors
Tyrosine kinase inhibitors
Antimetabolites
Simvastatin

Abbreviations

Amyloid β
AAV
Adeno-associated virus
ABL1
Abelson Murine Leukemia Viral Oncogene Homolog 1
AD
Alzheimer's diseases
AgNPs
Silver nanoparticles
AgTNPs
Silver triangular nanoplates
AICD
APP intracellular domain
AJs
Adherent junctions
Akt
Alpha Serine/Threonine-Protein Kinase
ALS
Amyotrophic lateral sclerosis
AMPK
AMP-dependent protein kinase
ApoE2
Apolipoprotein E2
ApoE3
Apolipoprotein E3
APP
Amyloid precursor protein
ARG
Abelson related gene
ATGs
Autophagy related genes
AuNPs
Gold nanoparticles
BACE
β-secretase enzyme
BBB
Blood-brain barrier
BDNF
Brain-derived neurotrophic factor
BECN1
Beclin 1
BE-MC
Baicalein loaded poly (ethylene glycol)-block-poly (D, l-lactide) micelles
BNIP3
BCL2 Interacting Protein 3
BRB
Berberine
CAMs
Coronary arterial myocytes
CDs
Carbon dots
c-kit
Stem-cell factor receptor
CML
Chronic myeloid leukemia
CNS
Central nervous system
CNTs
Carbon nanotubes
CPP
Cell-penetrating peptide
CSF
Cerebrospinal fluid
CTCL
Cutaneous T cell lymphoma
DAPK
Death associated protein kinase
DDR
Discoidin domain receptor
DHA
Docosahexaenoic acid
DLB
Dementia with Lewy bodies
ENL
Erythema nodosum leprosum
ERT
Enzyme replacement therapy
FKBP12
FK506 binding protein 12
FLT3
FMS-like tyrosine kinase 3
FRDA
Friedreich's ataxia
FTD
Frontotemporal dementia
GIST
Gastrointestinal stromal tumors
GJs
Gap junctions
GLUT1
Glucose transporter-1
GNRs
Gold nanorods
GQDs
Graphene quantum dots
GSAP
γ-secretase activating protein
HADC
Histone deacetylase
HCC
Hepatocellular carcinoma
HD
Huntington's disease
HDACIs
Histone deacetylase inhibitors
HMGCR
3-hydroxy-3-methylglutaryl-coenzyme A reductase
HTS
High-throughput screening
IP
Intraperitoneal
LC3
Light chain 3
Lck
Lymphocyte-specific protein
LSDs
Lysosomal storage diseases
MAPK
Mitogen-Activated Protein Kinase
MCI
Mild cognitive impairments
MEM
Memantine
mHtt
Mutant Huntington
MNPs
Magnetic nanoparticles
MQC
Mitochondrial quality control
mTOR
Mammalian target of rapamycin
mTORC1
Mammalian target of rapamycin enzymatic complex 1
mTORC2
mTOR complex 2
MWCNTs
Multi-walled carbon nanotubes
NDDs
Neurodegenerative diseases
NFTs
Neurofibrillary tangles
NPs
Nanoparticles
PAMAM
Poly(amidoamine)
PD
Parkinson's disease
PDGFR
Platelet-derived growth factor receptor
PI3K
Phosphoinositide 3-kinase
PKC
Protein kinase C
PLGA
Polylactide-co-glycolic-acid
PMLA
β-poly(L-malic acid)
PSEN1/PS-1
Presenilin 1
ptau
Phospho-tau
PTM
Posttranslational modifications
RCC
Renal cell carcinoma
Res
Resveratrol
rHDL
Reconstituted high-density lipoproteins
RVG
Rabies virus glycoprotein peptide
SGLT2
Sodium-glucose transport protein 2
SOD1
Superoxide dismutase 1
SWNT
Single-walled carbon nanotubes
TDP-43
TAR DNA-binding protein 43
TJs
Tight junctions
TKs
Tyrosine kinases
ULK1
Unc-51 like autophagy activating kinase 1 complex
UPR
Unfolded protein response
v-ATPase
Vacuolar ATPase
VLS
Virtual (in silico) ligand screening
ZAK
Zipper-containing kinase
ZBG
Zinc-binding group
αS
α-synuclein

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1

These authors have contributed equally to this work and share first authorship