write a mini-review about a specific research paper – a “News & Views”

Please see the attached.1. Primary Article2. Review article 1 for reference3. Review article 2 for referenceAddress the “what”s, “how”s, “why”s, “what next”s6-8 pages (double-spaced).Include: Introductory paragraph, background on area of research (including what was known before), experiments, conclusions and future experiments (unanswered questions).Include references (including to figures in the paper).You can refer to figures (and you can make you own figures).Need to focus primary research article.Students will use 1-2 review articles to supplement primary research article.International Journal of Nanomedicine
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Open Access Full Text Article
REVIEW
Alzheimer’s disease: pathogenesis,
diagnostics, and therapeutics
This article was published in the following Dove Press journal:
International Journal of Nanomedicine
Sneham Tiwari
Venkata Atluri
Ajeet Kaushik
Adriana Yndart
Madhavan Nair
Department of Immunology and NanoMedicine, Institute of NeuroImmune
Pharmacology, Herbert Wertheim
College of Medicine, Florida International
University, Miami, FL 33199, USA
Abstract: Currently, 47 million people live with dementia globally, and it is estimated to
increase more than threefold (~131 million) by 2050. Alzheimer’s disease (AD) is one of the
major causative factors to induce progressive dementia. AD is a neurodegenerative disease,
and its pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ)
plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in
cortical and limbic areas of the human brain. It is characterized by memory loss and
progressive neurocognitive dysfunction. The anomalous processing of APP by β-secretases
and γ-secretases leads to production of Aβ40 and Aβ42 monomers, which further oligomerize
and aggregate into senile plaques. The disease also intensifies through infectious agents like
HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aβ
peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity
of Aβ, microglia get activated, endocytose Aβ, and contribute toward their clearance via
TREM2 surface receptors, simultaneously triggering innate immunoresponse against the
aggregation. In addition to a detailed report on causative factors leading to AD, the present
review also discusses the current state of the art in AD therapeutics and diagnostics,
including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology
as an efficient therapeutic strategy to increase the bioavailability of drugs in the central
nervous system.
Keywords: amyloid beta, amyloidogenesis, amyloid precursor proteins, β-secretases, γsecretases, tau phosphorylation
Introduction
Correspondence: Madhavan Nair
Department of Immunology and NanoMedicine, Institute of NeuroImmune
Pharmacology, Herbert Wertheim
College of Medicine, Florida International
University, 11200 SW 8th Street, Miami,
FL 33199, USA
Tel +1 305 348 1493
Email nairm@fiu.edu
Alzheimer’s disease (AD) is a neurodegenerative and prominent proteinconformational disease (PCD)1,2 primarily caused by the aberrant processing and
polymerization of normally soluble proteins.3 When misfolded, soluble neuronal
proteins attain altered conformations, due to genetic mutation, external factors, or
aging, and aggregate, leading to abnormal neuronal functions and loss.4 AD’s
discovery as a neurodegenerative disease is attributed to Alois Alzheimer,
a German neurologist who examined a 51-year-old woman named Auguste Deter,
who was suffering with loss of memory, language, disorientation, and hallucinations. Her autopsy revealed plaques and tangles in the cerebral cortex,5 which
convinced him that this went beyond typical dementia. His discovery was followed
by further research that revealed the presence of neuritic amyloid β (Aβ) plaques in
dementia patients.6 Young onset of the disease is attributed to predisposition to PS1
genetic mutation, which is a rare but potent cause.7 Other neurodegenerative
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http://doi.org/10.2147/IJN.S200490
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Tiwari et al
diseases associated with abnormal protein conformations
are Parkinson’s disease, Creutzfeldt–Jakob disease,
Huntington’s disease, and Machado–Joseph disease,
which are caused by abnormalities in the α-synuclein,
Cellular Prion protein (PrPc), Scrapie prion protein (PrPSc
), Htt, and Ataxin3 proteins, respectively. Upon understanding the causal factors and pathogenesis mechanism of
the disease, it becomes of the utmost importance to
address such fields as AD mechanisms, pathogenesis, and
diagnosis, and finally how to design novel therapeutics
against it (Figure 1).
Diagnostic and imaging techniques include nanoparticle (NP)-based sensitive early-phase detection of AD biomarkers like Aβ and τ in cerebrospinal fluid (CSF)
samples from patients. Nanomaterials can also be used as
contrast agents for imaging aggregated Aβ plaques. It is
imperative to understand the role of NPs in increasing the
efficacy and bioavailability of the drug across the blood–
brainbarrier (BBB) into the central nervous system (CNS).
This review includes a detailed analysis of the pathogenic
pathway leading toward full-blown AD, addresses current
diagnostics and therapeutics available, and emphasizes the
potential role of nanotechnology in therapeutics against
disease progression.
AD pathogenesis
The field of research toward understanding AD pathogenesis
and designing efficient therapies is vast. AD is a highly
complex and progressive neurodegenerative disease.8 It is
one of the leading cause of dementia cases globally. In the US
alone, approximately 5.3 million Americans have AD, of
which 5.1 million are aged 65 years or older and 200,000
have younger-onset AD.9 Reported histopathological characteristics of AD are extracellular aggregates of Aβ plaques
and intracellular aggregations of neurofibrillary tangles
(NFTs), composed of hyperphosphorylated microtubuleassociated τ. Aβ plaques develop initially in basal, temporal,
and orbitofrontal neocortex regions of the brain and in later
stages progress throughout the neocortex, hippocampus,
amygdala, diencephalon, and basal ganglia. In critical
cases, Aβ is found throughout the mesencephalon, lower
brain stem, and cerebellar cortex as well. This concentration
of Aβ triggers τ-tangle formation, which is found in the locus
coeruleus and transentorhinal and entorhinal areas of the
brain. In the critical stage, it spreads to the hippocampus
and neocortex.10 Aβ and NFTs are considered the major
players in disease progression, and this review focuses on
the cause, pathogenesis, and factors associated with progression of AD.
Amyloid β and AD pathogenesis
Amyloid pathogenesis starts with altered cleavage of amyloid
precursor protein (APP), an integral protein on the plasma
membrane, by β-secretases (BACE1) and γ-secretases to produce insoluble Aβ fibrils. Aβ then oligomerizes, diffuses into
synaptic clefts, and interferes with synaptic signaling.11,12
Consequently, it polymerizes into insoluble amyloid fibrils
that aggregate into plaques. This polymerization leads to activation of kinases, which leads to hyperphosphorylation of the
microtubule-associated τ protein, and its polymerization into
insoluble NFTs. The aggregation of plaques and tangles is
followed by microglia recruitment surrounding plaques. This
promotes microglial activation and local inflammatory
response, and contributes to neurotoxicity.
Alzheimer’s disease
Understanding
mechanisms and
pathogenesis
Diagnostics and
imaging techniques
Treatment/drugs
Efficacy in drug
delivery:
nanotechnology
Figure 1 Overview of fields of research that need to be elucidated to understand the pathophysiology of Alzheimer’s disease and develop therapeutic strategies against it.
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Tiwari et al
Structure and function of APP
APP belongs to a family of associated proteins that includes
mammalian amyloid precursor like proteins (APLP1 and
APLP2), and Amyloid precursor protein-like (APPL) in
Drosophila. It is an integral transmembrane protein with extracellular domains (Figure 2). In a diseased state, APP generates
amyloidogenic fragments through differential cleavage by
enzymes.7 The physiological functions of APP remain less
understood. Studies with transiently transfected cell lines
show that APP moderates cell survival, growth, and motility,
along with neurite outgrowth and functions, which are attributed to the release of soluble ectodomains upon normal cleavage of APP.13,14 The importance of APP has been highlighted
by studies where neuronal abnormalities have been reported in
animals injected with APP RNAi,15 and APP-ectodomain
intracerebral injections have shown improved cognitive function and synaptic density.16 APP encodes type 1 transmembrane glycoprotein, which is cleaved either via
a nonamyloidogenic pathway (normal state) or via an amyloidogenic pathway (diseased state).17 APP releases various
polypeptides that arise possibly due to alternative splicing,
glycosylation, phosphorylation, or complex proteolysis.18,19
APP comprises 770 amino acids, of which Aβ includes 28
residues and an additional 14 residues from the transmembrane
domain of APP. At the cleavage site, α-secretase cleaves and
secretes large soluble ectodomain APPsα into the medium and
the C-terminal fragment C83 is retained in the membrane,
which is further cleaved by γ- secretase at residue 711, releasing soluble P3 peptide. Alternatively, in a diseased state,
abnormal cleavage is done by β-secretase releasing truncated
APPsβ and C-terminal fragment C99 is retained in the membrane and further cleaved by γ-secretase, releasing insoluble
Aβ peptides. Cleavage of both C83 and C99 by γ-secretase
releases the APP intracellular domain into the cytoplasm,
which is soluble and translocates to nuclei for further geneexpression function.5
Nonamyloidogenic pathway
APP undergoes constitutive and regulated cleavage. The αsecretase enzyme cleaves APP at residues 16–17 of the Aβ
domain and yield soluble and nonpathogenic precursors. In
neurons, ADAM10 and ADAM17 (metalloprotease) are
considered the major α-secretases. Processing by α-secretase
and γ-secretase generates the small hydrophobic fragment
p3, which is soluble and has a role in normal synaptic
signaling, but its exact functions are still to be elucidated.
It has been reported that cell-surface APP may get endocytosed as well, resulting in endosomal production of Aβ,
which leads to extracellular release and aggregation of Aβ.
The α-secretase processing releases the large soluble ectodomain APPsα, which acts a neuroprotective factor and also
has a role in cell–substrate adhesion. The presence of APPsα
associates with normal synaptic signaling and adequate
synaptic plasticity, learning, memory, emotional behavior,
and neuronal survival. Further, sequential processing
releases the APP intracellular domain, which translocates
into nuclei and facilitates nuclear signaling and geneexpression and -regulation pathways.20
Amyloidogenic pathway
APP is cleaved differently in the diseased state. Aβ is
released from APP through
sequential cleavages by BACE-1, a membrane-spanning
aspartyl protease with its active site situated in lumen, and γsecretase, an intramembrane aspartyl protease that is made
up of four proteins: presenilin, nicastrin, anterior pharynx-
Lumen
β
secretases
Cytosol
γ
secretases
α
secretases
γ40 γ42

Transmembrane domain
Figure 2 An overview of the Aβ-pathogenesis hypothesis.
Note: Amino-acid sequence of the Aβ fragment and location of action of α-, β-, and γ-secretases in diseased neurons within a diseased amyloidogenic pathway.
Abbreviation: Aβ, amyloid β.
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Tiwari et al
defective 1 (Aph1), and Psen2 complexed together.21 This
complex contributes to the activity of γ-secretase, which
produces insoluble and neurotoxic Aβ fragments. βsecretase cleavage is the first and rate-limiting step, making
a cut at the N-terminus of Aβ. It removes the majority of the
extracellular portion of the protein, leaving the C-terminal of
APP,22 which is further cleaved at the C-terminus of Aβ,
resulting in formation of the Aβ oligomers that further polymerize, forming aggregated plaques (Figure 3).
There are two main types of Aβ polymers that have
direct a role in plaque formation and induced neurotoxicity: Aβ40 and Aβ42. Aβ40 is abundant and less neurotoxic
than Aβ42, which is less abundant, highly insoluble,
severely neurotoxic, and more aggregation-prone and acts
as a toxic building fraction of Aβ assembly. Aβ40/Aβ42
aggregation results in blocked ion channels, altered calcium homeostasis, increased mitochondrial oxidative
stress, and diminished energy metabolism and glucose
regulation, which contributes to deterioration of neuronal
health and finally to neuronal cell death.
Hyperphosphorylation of τ and AD
AD is also characterized by the presence of NFTs. These
tangles are the result of hyperphosphorylation of the microtubule-associated τ protein.23 NFTs are fragments of paired
and helically wound protein filaments in the cell cytoplasm
of neurons and also in their processes. The τ protein has
a microtubule-binding domain and coassembles with tubulin
to form matured and stable microtubules.24,25 It has the
Nonamyloidogenic pathway (non-diseased)
γ-secretase
α-secretase
capability of stabilizing microtubules and forming interconnecting bridges between contiguous microtubules to form
a proper stable network of microtubules and hold them
together. When the τ protein comes into contact with the
kinases released, due to the abundance of Aβ in the environment, it gets hyperphosphorylated. Its hyperphosphorylation
leads to its being oligomerized. The tubule gets unstable, due
to dissociation of tubule subunits, which fall apart and then
convert into big chunks of τ filaments, which further aggregate into NFTs. These NFTs are straight, fibrillary, and highly
insoluble patches in the neuronal cytoplasm and processes,
leading to abnormal loss of communication between neurons
and signal processing and finally apoptosis in neurons
(Figure 4).26 It has been reported that soluble Aβ controls
cleavage and phosphorylation of τ for NFT generation.7
Further, phosphorylation of τ is regulated by several
kinases, including Glycogen Synthase kinase 3 (GSK3β)
and cyclin-dependent kinase 5 (CDK5) activated by extracellular Aβ. Even though GSK3β and CDK5 are primarily
responsible kinases for τ hyperphosphorylation, other
kinases like Protein Kinase C, Protein Kinase A, ERK2,
a serine/threonine kinase, caspase 3, and caspase 9 have
prominent roles too, which may be activated by Aβ.27
GSK3β and CDK5 in AD
GSK3β regulates the cleavage of APP carboxyterminal
fragments. Lithium and kenpaullone (two GSK3 inhibitors) prevent GSK3 expression and contribute to inhibition
of Aβ production.28 As such, GSK3 inhibitors might
Amyloidogenic pathway (diseased)
β-secretase
γ-secretase
Aβ aggregates
Cellular membrane
C83
APP
C99
AICD
Cytosol
Figure 3 Alternative splicing of APP in amyloidogenic and nonamyloidogenic pathways.
Note: Cleavage of APP by α- and γ-secretases in normal state and alternative cleavage by β- and γ- secretases in diseased state.
Abbreviations: C83, 83-amino-acid carboxyterminal; C99, 99-amino-acid membrane-bound fraction; AICD, APP intracellular domain.
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Tau
Aβ overproduction
Tau
mislocalization
to dendrites
Amyloid plaques
Spine loss
Tau hyperphosphorylation
Neurofibrillary
tangles
Neuronal damage and death
Figure 4 Hyperphosphorylationof τ.
Note: Mechanism by which τ hyperphosphorylation leads to instability of the
microtubule and finally microtubule subunits fall apart leading to formation of
insoluble and big neurofibrillary tangles.
Abbreviation: Aβ, amyloid β.
indirectly interfere with the generation of both Aβ plaques
and tangles in AD.
GSK3β activity in mitochondria has been associated with
increased oxidative stress.29 As such, GSK3β plays
a significant role in AD pathogenesis, contributing to Aβ
production and Aβ-mediated neuronal death by increasing
τ hyperphosphorylation. Additionally, it has been reported
that τ phosphorylation gets affected by Aβ–CDK5 interaction. This interaction leads to cleavage of adjacent proteins, releasing cleaved peptides with lower solubility and
longer half-lives, which may also phosphorylate distant
proteins. Substantial research focusing on identifying and
classifying kinases accountable for pathogenic τ hyperphosphorylation points toward the primary pathogenic kinases
GSK3β and CDK5, in addition to mitogen-activated protein kinase (MAPK), ERK1 and -2, MAP Kinase (MEK),
microtubule affinity-regulating kinase (MARK), c-Jun NH
(2)-terminal kinases (JNKs), p38, and PKA, among
others.30,31 Abnormal processing of APP leads to secretion
of Aβ, which affects GSK3 kinases, leading phosphorylation of the τ protein. This leads to aggregation of τ filaments that are insoluble and finally formation of huge
masses of NFTs in neurons.32
Genetic mutations: presenilin 1
mutation and AD
APP is not the only gene associated with AD. Presenilin
gene (PSEN1 and PSEN2), which are part of the γsecretase family, also mutate.33 Moreover, AD patients
may be predisposed to PS1 mutation leading to
familial AD at a young age.34 The γ-secretase complex is
International Journal of Nanomedicine 2019:14
made up of four proteins: Psen1, Psen2, Aph1, and nicastrin. Psen, an aspartyl protease, attributes to the catalytic
core of the complex. Psen2 facilitates the maturation of
PSEN, whereas Aph1 stabilizes the complex.35 Nicastrin
acts as a receptor for γ-secretase substrates. There are 179
PSEN1 and 14 PSEN2 gene mutations that participate in
early-onset autosomal-dominant AD. These mutations
favor production of more toxic forms of amyloid, eg,
Aβ42 as opposed to Aβ40, which contributes in disease
progression.36
Epigenetics and AD
Epigenetics deals with the study of interactions between genes,
expression of genotypes, and various molecular pathways that
modify genotype expression into respective phenotypes.37
Epigenetics exploring neurological diseases, neuroepigenetics,
has developed fairly well and been widely studied in CNSassociated diseases comprising learning, motor, behavior, and
cognition pathologies and disorders.38,39 Epigenetics is important to understand the depth of effect of environment or paternal genes, nutritional habits, trauma, stress or learning
disabilities, exposure to chemicals or drug addiction on DNA
and resultant structural disturbances, mutations, or
changes.40,41 The involvement of epigenetics has recently
been explored in one of the most complex aging-related neurological diseases — AD.42 The onset of AD and its progress
involves a complex interplay of various factors like aging,
genetic mutations, metabolic and nutritional disorders, effect
of and exposure to environmental variables, and most importantly the involvement of social factors.43 There is a fair chance
that factors in addition to aging, eg, hypertension, diabetes,
obesity, and inflammatory disorders, may h…
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