Accepted Manuscript

Sirtuin 1 and Alzheimer's disease: An up-to-date review

Liara Rizzi, Matheus Roriz-Cruz

PII: S0143-4179(18)30058-1
DOI: doi:10.1016/j.npep.2018.07.001
Reference: YNPEP 1883
To appear in: Neuropeptides
Received date: 15 March 2018
Revised date: 29 May 2018
Accepted date: 8 July 2018

Please cite this article as: Liara Rizzi, Matheus Roriz-Cruz , Sirtuin 1 and Alzheimer's
disease: An up-to-date review. Ynpep (2018), doi:10.1016/j.npep.2018.07.001

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 ACCEPTED MANUSCRIPT

Sirtuin 1 and Alzheimer’s disease: An up-to-date review

Liara Rizzi, MSc1,2,* ; Matheus Roriz-Cruz, MD, PhD1,2

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Division of Geriatric Neurology, Neurology Service, Hospital de Clínicas de Porto Alegre

(HCPA), Porto Alegre, RS, 90035-903, Brazil

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2
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,

RS, 90035-903, Porto Alegre, RS, 90035-903, Brazil

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*To whom correspondence should be addressed: NU
Name: Liara Rizzi

Address: R. Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil

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Telephone number: +55 51 985880443

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Email address: liaraa@yahoo.com.br

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Abstract

Sirtuins are NAD+-dependent enzymes that regulate a large number of cellular pathways and

are related to aging and age-associated diseases. In recent years, the role of sirtuins in

Alzheimer’s disease (AD) has become increasingly apparent. Growing evidence demonstrates

that sirtuin 1 (SIRT1) regulates many processes that go amiss in AD, such as: APP

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processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. Here we

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review how SIRT1 affects AD and cognition, the main mechanisms in which SIRT1 is related

to AD pathology, and its importance for the prevention and possible diagnosis of AD.

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Keywords: Sirtuins; SIRT1; Alzheimer’s disease; cognition; neurodegeneration.
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1. Research in Context

Sirtuins are nicotinamide adenine dinucleotide (NAD+) dependent enzymes

(Herskovits and Guarente, 2013). In terms of their evolution, they are highly conserved

proteins in both prokaryotes and eukaryotes (Amigo and Kowaltowski, 2014). This family of

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proteins shares a similar enzymatic domain of approximately 250 amino acids. They were

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originally identified as genetic silencing factors, for they were homologous to the silent

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information regulator (SIR2), initially identified in Saccharomyces cerevisiae (Nogueiras et

al., 2012). There are seven sirtuins (SIRT1-SIRT7) identified in mammals, which have been
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associated with caloric restriction and aging (Houtkooper et al., 2012). They are also

epigenetic modulators in several biological processes, such as cell metabolism and survival,
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senescence, proliferation, apoptosis, and DNA repair, as well as being commonly related to

ageing and age-associated diseases (Carafa et al., 2016; Jęśko et al., 2017).
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Sirtuins are structurally different in their sequence, length, and N- and C-termini,
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which may partly explain their different localizations and functions (Donmez and Outeiro,
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2013). Although some sirtuins may have redundant functions, their substrate specificities may
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be influenced by intracellular compartmentalization, different patterns of tissue expression,

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and distinct enzymatic activities (Herskovits and Guarente, 2013) (Table 1). Their activities

are intrinsically related to the cell’s energy state (Sanchez-Fidalgo et al., 2012). NAD+ levels

are increased in vivo in metabolic conditions such as fasting, caloric restriction and exercise.

In this sense, a low energy state (eg: fasting, caloric restriction, exercise) increases sirtuin

activity by increasing the NAD+/ NADH ratio. Conversely, a high energy state (eg:

postprandial) decreases sirtuin activity by decreasing NAD+ levels (Revollo and Li, 2013).
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The effects of sirtuins can be modulated by different activators (Dai et al., 2018; Fusi

et al., 2018). Fluctuations in the availability of NAD+ via an increase in its biosynthesis or via

non-allosteric methods that raise sirtuin levels, such as nicotinamide riboside and

nicotinamide mononucleotide, can module SIRT1 activity (Bonkowski and Sinclair, 2016).

The so-called sirtuin activating compounds (STACs) are a group of molecules that can

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increase sirtuins’ effects (Table 1) (Dai et al., 2018; Fusi et al., 2018; Jayasena et al., 2013).

The most potent molecule reported to date the well-known resveratrol, a polyphenol, but

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others molecules, such as curcumin, kaempferol, piceatannol, tannins, quercetin, and

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catechins may also be cited as molecules that increase sirtuins’ effects (Chung et al., 2010;

Dai et al., 2018; Donmez and Outeiro, 2013; Jayasena et al., 2013; Kemelo et al., 2017;
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Sawda et al., 2017). Resveratrol is a nutraceutical with several effects in neurological
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disorders (Jęśko et al., 2017). As a natural compound, it is found in many plants, including

grapes, peanuts, and berries. It has been shown to mimic the effects of caloric restriction,
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demonstrating anti-inflammatory and anti-oxidative effects, and to hinder the progression of

many diseases (Berman et al., 2017). Resveratrol is the main activator of SIRT1, one of the
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mammalian forms of the sirtuin family of proteins (Dai et al., 2018). Not only that, a number
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of chemicals, mostly analogs of resveratrol, have been reported to activate sirtuins, such as:
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SRT1720, SRT2104, 1,4-DHP derivative, UBCS039 (Bonkowski and Sinclair, 2016; Dai et
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al., 2018; Kumar et al., 2017). These were reported to be even more effective than natural

resveratrol in increasing SIRT1 enzymatic activity (Chung et al., 2010).

Age is the main risk factor for several neurodegenerative diseases; this remains true

even in individuals with elevated hereditary risk (Chen et al., 2014; Moussa et al., 2017).

Currently, the population is aging and, with that, there has been a proportional increase in the

incidence and prevalence of dementias, such as Alzheimer’s disease (AD) (Hugo and

Ganguli, 2014). Today, over 46 million people worldwide live with dementia, and this
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number is estimated to increase to more than 131 million by 2050 (Livingston et al., 2017).

AD is the main type of dementia and leads to severe cognitive impairment (Reitz and

Mayeux, 2014) (Box 1). Studies have shown that sirtuins’ hyperactivity could reduce AD

pathology in vivo and in vitro (Donmez et al., 2010), mainly by deacetylating substrates in

favor of the non-amyloidogenic pathway of AD or by acting directly on the classical proteins

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of AD pathology, β-amyloid and Tau (Wencel et al., 2017). In addition, sirtuins have been

shown to decrease neuroinflammatory processes, oxidative stress (Cornelius et al., 2013) and

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mitochondrial damages, which lead to, and aggravate, AD (Herskovits and Guarente, 2013).

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Despite several animal and cell culture studies, there has not been conclusive clinical studies

in humans, to this date.

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Box 1. Alzheimer’s disease (AD)
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AD is the most common neurodegenerative disorder, occurring mainly in

western and developed countries (Rizzi et al., 2014). Although age is the main risk
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factor for developing AD, it is a multifactorial disease, and age itself is not a

sufficient cause for developing the disease (Chen et al., 2014). Although some cases
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of AD are hereditary, sporadic development of AD is more common. Rare genetic

mutations, which can occur in the amyloid precursor protein (APP), in presenilin 1
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(PS1) or presenilin 2 (PS2) genes, can lead to familial early onset AD (Lanoiselée et
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al., 2017). AD is a heterogeneous disorder and the etiology of the sporadic form is

still unknown. It is postulated that it is caused by a complex interaction among aging,

several susceptibility genes, and environmental risk factors. The apolipoprotein E ε4

allele represents the major known genetic risk factor for late-onset AD. Those who

carry a copy of the ε4 allele are at greater risk for developing AD (Lim et al., 2018).

Those affected by AD undergo neurological dysfunction that results in memory loss

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and functional cognitive impairment as disease progresses (Raskin et al., 2015). The

pathological process tends to evolve slowly, and average survival after diagnosis is

short. It is characterized by diffuse and non-uniform cerebral atrophy (Gispert et al.,

2015). The pathophysiology of AD is triggered when protein processing occurs

incorrectly in the brain (Morley and Farr, 2014; Wang et al., 2013a). Under the

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microscope, there are toxic proteins in intra and extra neuronal spaces, which result in

progressive neuronal loss and synaptic dysfunction in specific cerebral regions

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(Humpel and Hochstrasser, 2011). In the initial stages, the medial temporal lobe is

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affected, and, therefore, areas involved in episodic memory are injured (Markesbery,

2010). Afterwards, AD reaches neocortical associative areas, responsible for

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language, reasoning, and social behavior. Over time, individuals with AD gradually
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lose the ability to live and function independently. Ultimately, AD could be fatal

(Braak and Braak, 1991; Kretzschmar, 2009). The lack of effective therapies which
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modify the natural course of the disease warrants a better understanding of its

pathophysiology, as well as new diagnostic tools (Blennow et al., 2015; Cummings et

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al., 2016; Cummings et al., 2017; Franco and Cedazo-Minguez, 2014; Reiman, 2017).
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AD is characterized by extracellular plaque deposits of the β-amyloid peptide

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as well as intraneuronal neurofibrillary tangles of the microtubule binding protein

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Tau, both of which lead to oxidative and inflammatory processes in the brain (Bloom,

2014; Godoy et al., 2014). β-amyloid peptides originate from proteolysis of the APP

by sequential enzymatic actions of β-secretase (also as known as beta-site amyloid

precursor protein–cleaving enzyme 1: BACE1) and γ-secretase (Box Fig. A) (Morley

and Farr, 2014; Panegyres, 1997; Querfurth and LaFerla, 2010). The peptides may,

under normal conditions, be degraded or eliminated by the cerebral spinal fluid

(CSF). However, an imbalance between production and clearance favors β-amyloid

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peptides to accumulate and aggregate, and, thus, this may be the initiating step for

developing AD (Barage and Sonawane, 2015). This idea, known as Amyloid

Hypothesis (Barage and Sonawane, 2015), proposed by John Hardy and David Allsop

in 1991 and reviewed by Tanzi and Bertram in 2005, is based on studies of the

hereditary variant of AD (Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Tanzi

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and Bertram, 2005). Alternatively, APP may be cleaved by α-secretase, generating

non-amyloidogenic peptides and liberating extracellular p3. The p3 peptide is known

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to have a role in AD; it is postulated to have a neuroprotective role, however this has

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not been clearly determined yet (Box Fig. B)(Han et al., 2011; Querfurth and LaFerla,

2010; Wencel et al., 2017).

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Tau proteins are microtubule-associated proteins involved in stabilizing
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neurons. In AD they become hyperphosphorylated. As phosphorylation increases,

Tau becomes insoluble and self-assembles into paired helical filaments, which form
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the neurofibrillary tangles. These destabilize neurons and lead to neurodegeneration,

increasing cognitive impairment severity (De-Paula et al., 2012; Wang et al., 2013a).
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(Please, insert Box Fig. here)

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2. Relationship between SIRT1 and AD

SIRT1 was the first to be identified and the most studied. It has been reported to be

involved in aging and longevity in animal models (Donmez, 2012). In addition, it is also

involved in many metabolic functions such as glucose homeostasis, lipid metabolism, energy

balance and stress. SIRT1 is detected in the nucleus and cytoplasm, and interacts with nuclear

and cytosolic proteins (Nogueiras et al., 2012). It is ubiquitously expressed in the brain, and is
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found mainly in areas related to neurodegenerative processes, such as the prefrontal cortex,

hippocampus, basal ganglia, cerebellum, hypothalamus, and, to a lesser extent, in the white

matter. SIRT1 is predominantly expressed in neurons (Donmez and Outeiro, 2013; Lattanzio

et al., 2014). SIRT1 catalyzes the deacetylation of several proteins by consuming NAD+,

generating nicotinamide (NAM), 2′-O-acetyl-ADP-ribose and the deacetylated substrate

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(Fig.1) (Bonda et al., 2011; Donmez and Outeiro, 2013; Revollo and Li, 2013). NAM is

recycled back into NAD+, and studies show that 2′-O-acetyl-ADP-ribose may play an

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important role in sirtuin biology, perhaps in acting additively or synergistically with the

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deacetylated substrate (Tong and Denu, 2010).
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Caloric restriction has been reported as preventing or procrastinating age-related

pathologies (Li et al., 2011; Srivastava and Haigis, 2011). Studies have shown that a caloric
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restriction of approximately 30-40% of one’s average caloric daily intake may regulate aging

by increasing longevity and reducing morbidity (Duan, 2013; Gräff et al., 2013; Ma et al.,
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2015). These benefits are due, at least in part, to the activation of sirtuins via an increase in

NAD+ levels (Chang and Guarente, 2014).

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Even though several studies have demonstrated the protective roles of sirtuin

activators as neuroprotective molecules in aging, little is known regarding the distribution or

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activity of SIRT1 in the aging brain (Braidy et al., 2015). Interestingly, studies have shown

that aging is associated with an increase in SIRT1 expression levels, but with a decreases in

their activity (Braidy et al., 2015; Conti et al., 2015). The decrease in SIRT1 activity is

consistent with the observed decrease in NAD+ levels during aging (Braidy et al., 2011;

Braidy et al., 2014). The oxidative stress produced during the aging process may lead to a

reduction in SIRT1 activity and in its control over certain proteins, therefore promoting

cellular senescence (Conti et al., 2015).

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In AD, an association between energetic metabolism and β-amyloid pathology is

suggested, since bioenergetic dysfunction was observed in the brain and in the peripheral

tissues of individuals diagnosed with AD (Martino Adami et al., 2017; Swerdlow, 2012).

Thus, considering that neurons are highly vulnerable to this dysfunction because of its high

energy demand, these alterations can lead to, or mediate, the pathology of AD (Silva et al.,

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2013). Although these mechanisms remain partly obscure, the activation of sirtuins, notably

SIRT1, may be a critical step in the pathogenesis of this disease, and, therefore, its

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modulation may aid in the prevention of AD. In this context, there are evidences of a

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connection between sirtuins and AD (Lalla and Donmez, 2013).
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Initially, studies in caloric restriction verified that the overexpression of SIRT1

reduced AD pathology (Imai and Guarente, 2010), wherein decreased formation of β-amyloid
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protein and senile plaques in transgenic mice was observed (Patel et al., 2005; Sanchez-

Fidalgo et al., 2012). It was also verified that resveratrol, acting as STACs, attenuated β-
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amyloid-induced cell death(Feng et al., 2013; Li et al., 2012; Porquet et al., 2014),

strengthened β-amyloid clearance (Marambaud et al., 2005), and barred memory loss by
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decreasing cognitive impairment (Porquet et al., 2013; Porquet et al., 2014). In a sample of

hungry squirrel monkeys, it was observed a reduction of β-amyloid deposition in their cortex,
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which correlated inversely with SIRT1 levels (Qin et al., 2006a).

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Later, it was demonstrated that mice overexpressing SIRT1 significantly reduced their

β-amyloid production, whereas cognitive deficits in SIRT1 knockout mice were aggravated

(Bonda et al., 2011). Additionally, the upregulation of SIRT1 and PGC-1α expression

improved learning and memory abilities in AD rats (Huang et al., 2018). In AD mice models,

treadmill exercise inhibited the production of β-amyloid via SIRT1, favoring the non-

amyloidogenic pathway of AD (Koo et al., 2017). In another study, there was an increase in

β-secretase mRNA levels in AD patients and in mice which developed AD, favoring the
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amyloidogenic pathway of β-amyloid formation, whereas SIRT1 mRNA levels were

decreased (Marques et al., 2012).

In vitro, SIRT1 overexpression, mediated by NAD+ or resveratrol, reduced the

oligomerization of β-amyloid peptides and decreased oxidative stress (Wang et al., 2010).

Moreover, poly (ADP-ribose) polymerase-1 (PARP1) inhibition (PARP-1, when

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overexpressed in AD, may lead to NAD+ depletion, followed by inhibition of SIRT1 activity)

activated SIRT1 expression in the presence of Aβ42 oligomers, upregulated α-secretase gene

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expression and, consequently, upregulated the non-amyloidogenic pathway (ADAM10) as

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well (Wencel et al., 2017). A model of AD cells showed
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SIRT1, was able to reduce astrocytes and pro-inflammatory mediators in AD (Scuderi et al.,

2014). A reduction in SIRT1 neuronal expression in human brain samples correlated inversely
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with the neuropathological changes of AD (Lutz et al., 2014). Overexpression of microRNAs

(e.g: miR-181) in a cellular model significantly decreased SIRT1 and contributed to AD

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neuropathology (Rodriguez-Ortiz et al., 2014). Also, diminished SIRT1 levels ran in parallel

to Tau protein accumulation (Min et al., 2010). Finally, in an autopsy study, a significant
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decrease in SIRT1 levels was observed in the parietal cortex of AD patients, which correlated

with the accumulation of Tau protein and with the duration of AD symptoms (Julien et al.,
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2009).
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The most common techniques currently used for detecting changes sirtuin (SIRT1-

SIRT7) level changes are polymerase chain reaction (PCR), western blotting,

immunohistochemistry, surface plasmon resonance and enzyme-linked immunoabsorbent

assays (ELISA) (Kumar et al., 2013; Lattanzio et al., 2014). Recently, in a multiplex-format, a

targeted mass spectrometric assay was developed and validated for the quantification of all

seven mammalian sirtuins. Quantification was made by multiple reaction monitoring and was

applied to a variety of samples including cultured brain cells, mammalian brain tissue, CSF
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and plasma (Jayasena et al., 2016). With this assay, studies reported that SIRT1 and SIRT2

were the most abundant sirtuins in cultured brain cells, with SIRT1 being the highest in

neurons (Jayasena et al., 2016). Indirectly, NAD+ and its related metabolites (NAD+

metabolome), as it is a regulator of sirtuin activity, can be successfully measured by liquid

chromatography coupled to mass spectrometry (Bustamante et al., 2017; Yaku et al., 2018).

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One study tested the hypothesis of using SIRT1 as a biomarker for AD. The

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researchers assessed serum concentration of SIRT1 in healthy individuals (young and old) and

in patients diagnosed with AD and mild cognitive impairment (MCI), using ELISA and

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surface plasmon resonance. They found a significant decline in SIRT1 serum concentration in
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patients diagnosed with AD and MCI when compared to elderly and young controls.

Moreover, SIRT1 concentration in healthy older patients was significantly lower compared to
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young healthy controls. Thus, the authors concluded that SIRT1 concentration decreases with

age, but in patients with MCI and AD the decline is more pronounced, which provides a basis
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for employing SIRT1 as a predictive marker of AD in its early stages (Kumar et al., 2013).
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Genetic studies have also aided in clarifying the molecular mechanisms underlying the
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etiology and pathogenesis of neurodegenerative diseases, including AD. Considering the

pleiotropic effects of SIRT1, its genetic variation in relation to the risks of human disorders
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and longevity might have been a field of interest. Interestingly, SIRT1 is located in a genetic

linkage region on chromosome 10(10q21.3), that is known to confer susceptibility for late-

onset AD (Albani et al., 2010). While SIRT1 is an interesting genetic target for association

analysis with AD, there are few genetic studies available, and most of them found no

significant association.

The relation of SIRT1 with late-onset AD was considered in a chromosome 10 genetic

screening in a British study, but the authors found no evidence to support the role of SIRT1 in
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AD risk (Morgan et al., 2007). This was confirmed in an independent Finnish study that

genotyped five SIRT1 SNPs (Helisalmi et al., 2008). Among the epigenetic studies, one

investigated SIRT1 gene expression and promoter DNA methylation patterns in post mortem

brain tissue from AD patients and healthy elderly subjects. They also found no differences

either in the expression or in the methylation of SIRT1 promoter sequences (Furuya et al.,

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2012).

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Despite this, a fresh input in the sirtuin-linked pathways and AD came from the

investigation of the genetic variability in sirtuin molecular targets. For instance, genetic

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analysis of the SIRT1 target, FOXO3A, found some evidence associating it with longevity
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(Albani et al., 2010). Moreover, the interaction between SIRT1 and ABCB1 SNPs appeared

to modify AD risk through alterations in beta-amyloid clearance (Hohman et al., 2016).

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Sirtuins are attractive therapeutic targets, and significant effort has been directed

towards developing specific activators as tools for understanding its function and potential
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treatments for diseases such as AD (Carafa et al., 2016; Dai et al., 2018). Even though studies
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have reported that natural and synthetic STACs have limited bioavailability and specificity
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(Dai et al., 2018; Fusi et al., 2018), and clinical studies remain scarce, a clinical trial showed

that resveratrol, as a STAC, can be safely used in patients with AD, and that it can alter the
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expression of AD biomarkers (Moussa et al., 2017; Turner et al., 2015). In patients diagnosed

with clinical AD confirmed by biomarkers, it was shown that resveratrol stabilized Aβ42 CSF

levels, and lowered its accumulation in the brain (Turner et al., 2015). Furthermore, it

decreased the levels of MMP-9, a matrix metalloproteinase that degrades components of the

extracellular matrix and whose activity is associated with neurodegeneration (Moussa et al.,

2017).
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3. Mechanisms of SIRT1 activity in AD

SIRT1 can modulate the pathology and the phenotype of AD by different mechanisms

(Table 2).

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3.1 Action in classical AD proteins: β-amyloid and Tau

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SIRT1 neuronal expression demonstrated to decrease levels of ROCK1, a

serine/threonine Rho kinase, previously shown to regulate β-amyloid metabolism by

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promoting the activity of the α-secretase enzyme (Feng et al., 2013). Therefore, SIRT1
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prevents the formation of β-amyloid oligomers and senile plaques by inducing the APP

processing for the non-amyloidogenic pathway (Koo et al., 2017; Qin et al., 2006b). Another
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mechanism of action of SIRT1 was observed when its overexpression decreased amyloid

plaque burden and improved behavioral phenotypes via the deacetylation of RARβ (retinoic
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acid receptor β), a transcriptional activator of ADAM10 (disintegrin and metalloproteinase

domain-containing protein 10). ADAM10 is a component of the α-secretase enzyme, which

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processes APP through the non-amyloidogenic pathway and decreases formation of toxic β-

amyloid (Donmez et al., 2010; Lee et al., 2014; Theendakara et al., 2013). Moreover,
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ADAM10 is known to start the Notch pathway via membrane-bound Notch receptor cleavage.
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This mechanism releases an intracellular domain that increases the transcription of genes

involved in neurogenesis (Bonda et al., 2011). The overexpression of SIRT1 directly reduced

amyloid plaques, while the elimination of SIRT1 increased plaque formation (Donmez, 2012).

SIRT1 may directly deacetylate Tau proteins, which leaves them susceptible to ubiquitin

ligases. They can then be degraded into multiple residues, diminishing the formation of

neurofibrillary tangles and suppressing the spread of Tau-induced pathology in vivo (Min et

al., 2010; Min et al., 2018).

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3.2 Action in other mechanisms related to AD

Studies have shown that SIRT1 protects against microglia-dependent β-amyloid

toxicity by inhibiting NF-κB (nuclear factor kappa B) signaling, which, in turn, decreases

neuroinflammation (Chen et al., 2005). Leptin, an appetite-controlling hormone, increased

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SIRT1 expression and activity while decreasing NF-κB-mediated expression of BACE1. This

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mechanism demonstrates that the leptin-SIRT1-NF-kB cascade is involved in the regulation

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of BACE1 expression, and, consequently, with the decrease of β-amyloid production

(Marwarha et al., 2014). By deacetylation and activation of Peroxisome Proliferator-activated

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Receptor Gamma Coactivator 1-alpha (PGC-1α), SIRT1 promoted mitochondrial biogenesis

and prevented mitochondrial dysfunction in AD (Donmez, 2012; Koo et al., 2017). Moreover,
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a potent suppressive effect of key transcriptional regulators of BACE1 was detected via

activation of SIRT1-PPARγ-PGC-1α (Wang et al., 2013b).

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Studies with Positron Emission Tomography (PET) showed that regions where
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amyloid plaques and AD neurodegeneration are typically found are similar to regions in
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which glucose is metabolized via aerobic glycolysis (Vlassenko et al., 2010). With this,
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Bonda et al. suggested a possible relationship with AD. The energy-demanding regions of the
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brain, most notably the medial temporal lobe, resort to aerobic glycolysis as an alternating

mean of generating ATP. As a result, NAD+ pool is depleted and, consequently, SIRT1

becomes hypoactive. The downregulation of SIRT1 reduced APP processing via α-secretase,

favoring the amyloidogenic pathway via β-secretase, and amyloidogenesis. However, the

authors point out that this mechanism should still be tested more thoroughly (Bonda et al.,

2011).
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4. Concluding remarks

It is now clear that sirtuins, especially SIRT1, are connected to AD by many different

mechanisms, including those involved in APP processing, neuronal inflammation and

degeneration, and mitochondrial dysfunction. In these contexts, the action of SIRT1 may

suppress AD pathology by different pathways. Chemical or metabolic activators of SIRT1 can

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manipulate sirtuins levels and offers the possibility of regulating the disease coordinately. It is

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likely manipulating SIRT1 activity will have an important role in AD therapy by itself or in

combination with drugs. Besides, the development of more accurate assays for measuring

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SIRT1 could aid in diagnosing AD in a more timely manner, which, in turn, will help in
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fighting this deadly disease in the future.
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5. Acknowledgements
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This study was supported by FIPE (Project number: 17-0084). All authors declare that
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their funding source had no role in the study design, analysis and interpretation of data, in the
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writing of the report, and in the decision to submit the paper for publication.
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6. Disclosure statement

The authors hereby declare that there are no actual or potential conflicts of interest that

may have affected the discussion presented.

7. Authors’ Contributions:
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LR and MRC contributed to the study concept and design, to the acquisition, analysis

and interpretation of data, and to the preparation of the manuscript. All authors approved the

final article.

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Table 1. Characterization of Sirtuin Proteins.

Mammalian Molecular Mass Enzymatic Activity Cellular STACs

Sirtuins (KDa) Localization

SIRT1 81.7 deacetylase Nuclear, cytoplasmic Resveratrol,

quercetin,
butein,
catechins

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piceatannol,
SRT1720,

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SRT2104,
1,4-DHP

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derivative
SIRT2 43.2 deacetylase Nuclear, cytoplasmic Resveratrol,
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SIRT3 43.6 deacetylase Mitochondrial Resveratrol,
Kaempferol,
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piceatannol
SIRT4 35.2 ADP- Mitochondrial Not known
ribosyltransferase
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SIRT5 33.9 deacetylase Mitochondrial Resveratrol,

demalonylase Piceatannol,
dessuccinylase UBCS039
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SIRT6 39.1 ADP- Nuclear UBCS039

ribosyltransferase
deacetylase
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SIRT7 44.8 deacetylase Nucleolar Resveratrol

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*SIRT: sirtuin; STACs sirtuin activating compounds . Adapted from (Chung et al., 2010; Dai et al., 2018; Donmez and
Outeiro, 2013; Jayasena et al., 2013).
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Table 2. SIRT1 targets in AD.

Interacts Type of Significance of SIRT1 Action Biological Relevance in AD

with/ Interaction
Substrate
ROCK1 Downregulation Promotes α-secretase pathway Decreases β-amyloid production
Activation of ADAM10 Decreases β-amyloid production
RARβ Deacetylation Upregulation of Notch signaling Involved in neurogenesis

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β-amyloid Downregulation Avoids β-amyloid aggregation Reduces amyloid plaques

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Tau Deacetylation Tau proteins are degraded by ubiquitins Reduces the formation of NFT
Protects against microglia-dependent β-amyloid Decreases neuroinflammation

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NF-κB Deacetylation toxicity
Downregulation of BACE1 Decreases β-amyloid production
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PGC-1α Deacetylation Promotes mitochondrial biogenesis Avoids mitochondrial dysfunction
PPARγ Deacetylation Increases PGC-1α Downregulation of BACE1
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*ADAM10: Disintegrin and Metalloproteinase Domain-containing Protein 10; BACE1: beta-site amyloid precursor protein-cleaving
enzyme 1; NF-κB: Nuclear Factor Kappa B; NFT: Neurofibrillary Tangles; PGC-1α: Peroxisome Proliferator-activated Receptor
Gamma Coactivator 1-alpha; PPARγ: Peroxisome Proliferator-activated Receptor Gamma; RARβ: Retinoic Acid Receptor β;
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ROCK1: Serine/Threonine Rho Kinase; SIRT1: Sirtuin 1.

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Figure Captions

Box Fig. Processing of APP. A) Proteolysis of APP by sequential enzymatic actions of β-

and γ-secretases, generating sAPPβ peptides and liberating Aβ 42. B) Proteolysis of APP by α-

secretase, generating sAPPα peptides and liberating extracellular p3 peptide.*Aβ: β-amyloid;

APP: Amyloid Precursor Protein.

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Fig.1 Enzymatic reaction catalyzed by SIRT1. SIRT1 catalyzes the deacetylation of

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proteins by consuming NAD+, generating nicotinamide (NAM), 2′-O-Acetyl-ADP-Ribose

and the deacetylated substrate.*Ac:Acetyl; NAD+: nicotinamide adenine dinucleotide; NAM:

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nicotinamide; SIRT1: Sirtuin 1.
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Highlights

 Sirtuins are related to aging and age-associated diseases;

 SIRT1 plays important regulatory roles in AD by different mechanisms;
 The effects of sirtuins can be modulated by activating compounds;
 SIRT1 could aid in the diagnosis and in the prevention of AD.

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Figure 1