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Файл:Age endocrinology. Study aid for students of medical universities
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sensitivity, accumulation of beta-amyloid (Aβ), tau hyperphosphorylation, vascular
damage, and inflammation.
AD is a chronic neurodegenerative disease that usually starts slowly and
worsens over time. It is the cause of 60–70 % of dementia cases. The most common
early symptom is difficulty remembering recent events (short-term memory loss). As
the disease progresses, symptoms may include speech problems, disorientation, mood
swings, loss of motivation, inability to self-care, and behavioral problems. This
progressive neurodegenerative disease is characterized by the accumulation in the
brain of extracellular neuritic plaques and fibrils (mainly composed of aggregated
amyloid β-Aβ peptides), intracellular neurofibrillary tangles (accumulation of
hyperphosphorylated tau-NFTs proteins), microglial infiltration, cerebral atrophy,
and widespread loss of synaptic and neuronal transmission. Severe
neuroinflammation is also consistently seen in AD. Research data have shown that
hyperactivity of pro-inflammatory markers in the brain precedes the development of
plaques and neurofibrillary tangles in AD.
A number of pathophysiological links have been found between AD and
metabolic disorders such as T2DM, obesity, and metabolic syndrome. In contrast to
the small number of cases of AD (~3 %) due to hereditary genetic causes, the
pathogenesis and etiology of late-onset sporadic AD is multifactorial, involving
genetic and lifestyle factors. The recognition of T2DM as a major risk factor for
dementia, especially AD, has prompted researchers to search for underlying
mechanisms linking these two age-related chronic diseases. It is known that
metabolic disorders characteristic of T2DM (eg, hyperglycemia, hyperinsulinemia,
hypercholesterolemia) are associated with brain atrophy and pathological features of
AD. Whether insulin resistance is a cause or a consequence of AD is not yet clear.
Moreover, a number of researchers support the idea that dysregulation of the
insulin signaling system may be a key factor contributing to the early development of
AD. For example, some scientists have shown that the expression and activation of
IR, IGF-1R and IRS-1 proteins is reduced in the brains of AD patients compared with
the control group. Moreover, several authors have demonstrated that neocortical
insulin levels and IR binding are reduced in the brains of AD patients. Finally, a
lower cerebrospinal fluid insulin concentration, despite a higher plasma insulin
concentration, suggests reduced insulin action in the central nervous system.
The amyloid plaques found in the brains of AD patients are primarily
composed of Aβ, a peptide derived from a larger molecule known as amyloid
precursor protein (APP). An imbalance between production, clearance, and
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aggregation of peptides causes accumulation of Aβ, and this excess may be an
initiating factor for the development of AD.
A number of researchers have proposed a link between defects in energy
metabolism and functional changes associated with the development of AD.
Inhibition of energy metabolism can alter the APP process and induce the production
of amyloidogenic products. The relationship between insulin and Aβ metabolism has
recently attracted increasing attention from scientists.
Small Aβ oligomers are known to promote synaptotoxicity and subsequent
changes that lead to neurodegenerative processes in AD. As part of these
neurodegenerative processes, Aβ oligomers appear to have a negative effect on
insulin signaling by inhibiting receptor autophosphorylation and markedly decrease
IR levels and activity on the cell surface of hippocampal neuron dendrites. IRs play a
key role in important neurological processes, including learning and memory, as well
as tau phosphorylation. Thus, Aβ oligomer -induced loss of membrane IRs may
represent an important early mechanism underlying memory impairment and other
pathological disorders in AD.
Aβ oligomers have also been found to determine aberrant activation of
TNFα/JNK and IRS-1 inhibition in both in vitro and in vivo models. In addition, Aβ
oligomers also influence downstream IRS-1 and PI3K signaling, where they can
activate Akt serine phosphorylation and stimulate inflammatory processes. On the
other hand, insulin resistance is known to accelerate the production of Aβ,
contributing to its accumulation. When insulin resistance is induced in AD transgenic
or obese diabetic mice by feeding them a high-fat diet, the mice show elevated levels
of Aβ in the brain and increases in levels of key enzymes that generate Aβ (e.g., γsecretase). Finally, insulin and Aβ are substrates of the insulin degrading enzyme, and
it has been proposed that hyperinsulinemia inhibits Aβ degradation by competitively
blocking the insulin degrading enzyme.
10.4. IMPAIRMENT IN THE INSULIN SIGNALING SYSTEM
OF THE BRAIN AND HYPERPHOSPHORYLATION OF TAU
Deficiency in insulin signaling can also exacerbate neurodegeneration by
increasing phosphorylation of tau, which is a neuronal microtubule protein found in
axons. It plays an important role in the assembly and stability of microtubules, as
well as in the transport of vesicles in neurons. In AD, hyperphosphorylation of the tau
protein is an important pathological feature and contributes to neuronal dysfunction
and degeneration. Insulin and IGF-1 have been shown to regulate tau phosphorylation
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by inhibiting GSK-3β in cell culture neurons. GSK-3β is a key kinase that
phosphorylates the tau protein. Deficiencies or abnormalities in insulin signaling in
the brain lead to a decrease in Akt activity, leading to an increase in GSK-3β activity.
This phenomenon causes tau hyperphosphorylation and hence the formation of tau
fibrils. Moreover, peripheral hyperinsulinemia promotes tau phosphorylation in vivo.
It has been demonstrated that upon deletion of the IGF-1 and IRS-2 gene, tau
phosphorylation is dramatically increased in IGF-1 and IRS-2 knockout mice. Indeed,
the genetic deletion of IGF-1 specifically increases tau phosphorylation at two GSK3β target loci. These results suggest that normal insulin and IGF-1 signaling prevents
tau hyperphosphorylation in the brain. Given that T2DM is characterized by insulin
resistance, hyperinsulinemia, and impaired insulin signaling, it is not surprising that
increased GSK-3β activity in T2DM may lead to increased Aβ production and
increased tau phosphorylation.
Insulin can also regulate tau expression, and decreased insulin signaling can
lead to disruption of tau gene expression, resulting in decreased levels of normal
soluble tau, while hyperphosphorylated tau accumulates, exacerbating neuronal
cytoskeletal collapse, neurite retraction, and abnormalities in synapse formation.
Moreover, it has been demonstrated that AD -associated reduction in mRNA
expression tau correlates with impaired insulin and IGF-1 signaling observed in the
same AD samples, demonstrating a strong association between the two mechanisms.
10.5. INSULIN RESISTANCE, CEREBRAL VASCULOPATHY
AND NEUROINFLAMMATION
Neurodegenerative disorders and T2DM are characterized by both vascular
damage, decreased cerebral blood flow, and an aberrant inflammatory response.
It has been shown that patients with AD have a decrease in regional cerebral
blood flow, which can lead to a decrease in the supply of oxygen, glucose and
nutrients to the brain. This phenomenon is associated with disruption of the insulin
transduction pathway. The insulin signaling system is involved in the regulation of
vasodilation and vasoconstriction. IR activation mediates vasodilation via the
PI3K/Akt pathway. It stimulates endothelial nitric oxide synthase (eNOS), resulting
in nitric oxide (NO) production and vascular relaxation. In the insulin resistant state,
there is a specific disruption of the PI3K vasodilator pathway, resulting in decreased
NO production and hence vasoconstriction. As a result, there is a decrease in the
supply of nutrients to the brain, an increase in oxidative stress and ROS production,
and, consequently, an activation of the inflammatory response. The release of pro-
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inflammatory cytokines and recruitment of macrophages provoke atherosclerosis,
which ultimately leads to macrovascular complications.
It is well known that chronic inflammation processes are a major part of the
pathogenesis of T2DM as well as neurodegenerative diseases. A number of
researchers have proven that induced chronic inflammation is an important early
stage in the pathogenesis of AD.
It has been shown that hyperinsulinemia contributes to the development of
inflammation processes in the central nervous system. It has been established that an
increase in the level of peripheral insulin leads to an increase in the levels of proinflammatory cytokines in the brain, such as interleukin-1 (IL-1), interleukin-6 (IL-6)
and tumor necrosis factor-α (TNF-α), elevated during AD and localized in amyloid
plaques and associated glial cells.
In peripheral insulin resistance, production of inflammatory cytokines and
activation of inflammatory stress signaling can lead to serine phosphorylation of
IRS-1 by kinases, kappa-B-kinase inhibitor (IKK), c-Jun N-terminal kinase (JNK),
and ERK2, which, in turn, it disrupts IR-mediated signaling by blocking the
intracellular action of insulin. A similar mechanism is hypothesized to occur in the
brain, where Aβ oligomers can activate microglia, resulting in the secretion of proinflammatory cytokines that bind to their respective receptors, activating one or more
IRS-1 serine kinases and in turn phosphorylating the IRS. Elevated levels of vascular
pro-inflammatory cytokines, seen in both T2DM and AD, may also influence insulin
signaling in the brain. When brain tissue is damaged, cytokines can cross the bloodbrain barrier and activate IRS-1 phosphorylation.
Vascular inflammation can also be mediated by the activation and increase in
glycation end product (RAGE) receptors. RAGE is expressed in neuronal cells,
microglial astrocytes, and brain endothelial cells, and is elevated in both AD and
T2DM. Elevated levels of RAGE have been proposed as a possible mechanism for
vascular dysfunction in both T2DM and AD, and the interplay between impaired
cerebral glucose metabolism, oxidative stress, and glycation end product
accumulation plays an important role in the vicious cycle that promotes the
progression of AD, RAGE is receptor-mediated Aβ transport across the blood-brain
barrier from the periphery to the brain, inducing cerebrovascular dysfunction leading
to neurovascular stress, TNF-α and IL-6 production, promoting synaptotoxicity and
neurodegeneration.
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10.6. THE POLYPATENT ROLE OF GLP-1
GLP-1, produced from the gut, activates GLP-1R, located on the vagus sensory
neurons that make up the hepatoportal glucose sensor, binds to brainstem neurons,
spreading its action to various areas of the brain. Several studies have shown a range
of actions of this peptide on neurons such as thermogenesis, blood pressure control,
neurogenesis, neurodegenerative changes, retinal repair, and energy homeostasis.
Since GLP-1R is expressed in different areas of the brain, GLP-1 behaves like a
neuropeptide involved in a variety of specific effects, including satiety control, water
intake, and the stress response. Kinzig et al. (2003) found that GLP-1-stimulated
brain GLP-1Rs trigger multiple stress responses. Thus, administration of GLP-1
directly into the rat brain increased anxiety levels associated with higher production
of stress-activated hormones (ACTH, cortisol), demonstrating that GLP-1 was able to
simultaneously stimulate both amygdala and paraventricular nucleus responses.
hypothalamus. An increase in the concentration of GLP-1 in the peripheral
circulation regulates the feeling of hunger and satiety. Recent studies have shown that
GLP-1 in combination with dexamethasone (GLP-1/Dexa) can reduce food intake
and reduce body weight in obese mice without causing mood or memory deficits. In
T2DM, changes in insulin sensitivity and impaired neurogenesis correlate with
decreased levels and signaling activity of GLP-1 in response to food intake.
Muscogiuri et al., 2017 showed that GLP-1 is involved in the regulation of
neurological and cognitive functions. Indeed, GLP-1 is also involved in the control of
synaptic plasticity and some forms of neuroprotection, and thus plays a regulatory
role in various signaling pathways associated with learning, memory, and other
functions.
10.7. GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
AS NEUROPROTECTIVE AGENTS IN T2DM-ASSOCIATED
COGNITIVE IMPAIRMENT
T2DM is a chronic disease with a growing prevalence worldwide. In addition
to the well-known micro- and macrovascular complications, cognitive decline is
believed to be an emerging consequence of diabetes.
Over the past decade, GLP-1RAs have become effective hypoglycemic drugs
that normalize blood glucose levels. Exenatide was the first GLP-1RA approved for
the treatment of T2DM. It is a synthetic form of exendin-4, a naturally occurring
GLP-1-like peptide isolated from the saliva of the lizard Heloderma suspectum.
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Exenatide is 53 % similar to native GLP-1. Exenatide has a half-life of 2.4 hours,
while GLP-1 has a half-life of 2 minutes. Lixisenatide is based on the structure of
exendin-4 with a half-life of 3 hours. Liraglutide was the first GLP-1RA derived from
native GLP-1, with 9 7% homology and a half-life of 13 hours. Semaglutide, a
modified form of liraglutide, has a half-life of ~7 days due to a 5.6-fold affinity for
albumin compared to liraglutide.
The neuroprotective effects of GLP-1RA have been studied in several animal
studies with T2DM. Many of them analyzed the effect of GLP-1RA on
ischemia/reperfusion injury of the brain. In T2DM rats with cerebral ischemia caused
by middle cerebral artery occlusion, recombinant GLP-1 improved neurological
deficits and reduced cerebral infarct area, mainly by inhibiting oxidative stress and
apoptosis. In addition, GLP-1RAs have beneficial effects in reducing cognitive
impairment caused by diabetes or obesity.
Indeed, it was noted that peripheral administration of lixisenatide for 40 days
(50 nmol/kg bw, twice daily) in obese mice with insulin resistance and cognitive
impairment resulted in a marked improvement in memory, which was associated with
an increase in the expression neurotrophic tyrosine kinase receptor type 2 and
rapamycin (mTOR) genes in the hippocampus involved in modulating synaptic
plasticity and pre-LH-term potentiation. Treatment with lixisenatide also promoted
the proliferation of hippocampal progenitor cells and an increase in the number of
immature neurons in the dentate gyrus of the hippocampus. Liraglutide has
demonstrated anti-neurodegenerative effects of the hippocampus in animals with
streptozotocin-induced diabetes (STZ), and neurodegeneration with cognitive decline.
In particular, liraglutide improved learning and memory and reduced the death of
hippocampal neurons. In addition, in mice with STZ-induced diabetes, treatment with
liraglutide reduced neuronal and synaptic damage in the CA1 region of the
hippocampus.
It is noteworthy that the neuroprotective activity of GLP-1RA, apparently, is
associated not only with the normalization of glycemia. Indeed, there is increasing
evidence of the neuroprotective effects of GLP-1RA in animal models of
neurodegenerative diseases without diabetes mellitus. Liraglutide reduced brain
infarct size in diabetic and non-diabetic rats, but reduced neurological deficits only in
non-diabetic rats, suggesting that the cognitive effects of GLP-1 RA are unrelated to
diabetes compensation and glycemic normalization. Indeed, both metformin (a nonpancreatic hypoglycemic drug acting through AMP-activated protein kinasedependent pathways) and liraglutide induced euglycemia in diabetic rats, but only
liraglutide therapy reduced ischemic brain injury.
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10.8. GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS
AS NEUROPROTECTORS IN COGNITIVE IMPAIRMENT
ASSOCIATED WITH NEURODEGENERATIVE DISEASES
An association has been proven between T2DM and neurodegenerative
diseases such as Parkinson's disease (PD) and AD. Neurodegenerative diseases have
a significant physical, psychological, social and economic impact, both on the
patients themselves and on society as a whole.
Parkinson's disease
Parkinson's disease is a progressive disease of the nervous system, the etiology
of which is still unclear, although genetic and environmental factors seem to play a
significant role. Clinical features of PD include resting tremor, slow movement
(bradykinesia), postural instability, and loss of purposeful movement. Pathological
features are characterized by damage to the neurons of the compact substantia nigra
with the formation of intracellular Lewy bodies and the loss of dopaminergic
neurons. Lewy bodies are abnormal aggregates of the protein α-synuclein, which is
involved in the metabolism and function of dopamine. Dysfunction of dopaminergic
neurons and their death from apoptosis or autophagy are also associated with a
decrease in mitochondrial activity, oxidative stress, and the inflammatory response. A
rare dominant familial form of PD is associated with point mutations, duplications,
and triplications in the α-synuclein gene.
In various preclinical PD models, GLP-1RA has shown neuroprotective effects
affecting locomotor activity, dopaminergic neurons, cortical activity, and energy
metabolism in the brain. Harkavyi et al. analyzed the efficacy of exendin-4 in PD rats
treated with 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS). The
analysis showed that in striatal tissue dopamine concentrations were markedly higher
in 6-OHDA/LPS + exendin-4 rats compared to 6-OHDA/LPS + placebo. This effect
was associated with an increase in the enzyme tyrosine hydroxylase involved in the
production of l-dopa, a precursor to dopamine. In the same PD rats, exendin-4
stimulated adult neurogenesis in vitro and in vivo by normalizing dopamine
imbalances, increasing tyrosine hydroxylase and vesicular monoamine transporters in
the substantia nigra. Other authors have noted that administration of exendin-4,
liraglutide, and lixisenatide to mice prevented both motor dysfunction and decreased
levels of tyrosine hydroxylase in the substantia nigra and basal ganglia. In addition,
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liraglutide and lixisenatide induced a marked increase in anti-apoptotic pathways
compared to exendin-4.
Long-term administration of liraglutide was found to reduce dopaminergic
neuronal loss and motor failure also in db/db diabetic mice, a known model of
diabetes, with a mutation in the gene encoding the leptin receptor. In addition, the
authors suggested that long-term administration of liraglutide could prevent motor
impairment and the development of PD also in patients with T2DM. In a rotenoneinduced PD model, liraglutide, together with sitagliptin, a DPP IV inhibitor, increased
striatal dopamine and tyrosine hydroxylase protein levels, reduced
neuroinflammation, and decreased neuronal loss. Liraglutide may also reduce
dyskinesia, a serious complication of long-term l-dopa therapy.
In mice with PD, semaglutide improved the clinical picture of PD by reversing
motor impairment, causing an increase in tyrosine hydroxylase levels, and attenuating
neuroinflammation and apoptosis in the substantia nigra and striatum. Following this
treatment, there was a decrease in α-synuclein aggregation that was not seen with
other GLP-1RAs, indicating that semaglutide is an effective treatment for PD.
Preliminary clinical studies with exenatide have been performed in patients
with PD. Atauda and et al. (2017) reported the results of the first randomized, doubleblind, placebo-controlled trial in 62 patients with moderate PD. For 48 weeks,
patients received exenatide 2 mg subcutaneously once a week (#32) or placebo (#30).
After 12 weeks of therapy, exenatide showed a positive sustained effect on clinically
assessed motor function. Post hoc analysis showed that symptoms even without
motor, such as clinically assessed mood and emotional well-being, improved in
patients treated with exenatide although these positive effects did not last after a
break. Patients treated with exenatide had significantly higher insulin receptor
substrate 1 (IR) tyrosine phosphorylation and higher expression of total Akt and
phosphorylated mTOR than patients treated with placebo, which is a possible
explanation for the normalization of insulin action and improved clinical picture.
Alzheimer's disease
Dementia is a chronic disease that affects memory, other cognitive abilities and
behavior. It is estimated that around 50 million people worldwide have dementia. It is
currently the seventh leading cause of death and one of the leading causes of
disability. Pre-diabetic risk factors, obesity, and metabolic syndrome may contribute
to cognitive dysfunction. AD is the most common form of dementia, accounting for
60–70 % of cases. The main neuropathological features of AD are neurofibrillary
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tangles formed by hyperphosphorylated tau proteins that aggregate into oligomers
and amyloid plaques composed of aggregated β-amyloid peptides (Aβ).
A large amount of evidence suggests a link between T2DM and AD. In
particular, both nosologies may share common impairments in insulin signaling.
Interestingly, mice with a genetically induced AD-like neuropathology (3xTg- AD
mice) showed intolerance to administered glucose. Treatment with pioglitazone, a
glucose-lowering drug, significantly improved cognitive impairment in these mice,
supporting a neurotrophic role for insulin. In the same mice, a high-fat diet further
exacerbated the disturbance of carbohydrate metabolism and the neuropathological
clinical features of AD (memory deficit). Insulin administration reversed the negative
effects of a high-fat diet, breaking the vicious circle between diabetes and AD. Both
studies revealed the neurotrophic role of insulin in the brain.
Conversely, hyperinsulinemia induced by peripheral insulin administration
increased tau phosphorylation in C57BL/6 mice.
Aggregated β-amyloid peptide oligomers induced a decrease in the activity of
insulin receptors (IRs) due to phosphorylation of IRS-1 at serine residues (IRS-1pSer)
with subsequent loss of substrate affinity, as observed in T2DM. A number of authors
believe that in mouse hippocampal neurons, Aβ oligomers activate TNF-α/JNK
signaling, inducing insulin resistance. GLP-1RAs not only prevent JNK/IKK
activation, but also stimulate insulin activation by the PI3K/AKT axis, followed by
activation of mTOR and the GSK-3β block, an essential kinase also involved in tau
protein phosphorylation. Ma D. et al. (2015) reported that liraglutide administration
prevented aging-associated tau hyperphosphorylation in db/db diabetic mice.
The role of vascular dysfunction is an essential factor in the pathophysiology of
AD. The decrease in cerebral blood flow may precede the formation of Aβ oligomers
and tau deposition, and this is associated with cognitive impairment. In APP/PS1
transgenic mice, liraglutide reduced the incidence of cerebral microaneurisms and
improved blood flow.
Glucagon-like peptide-1 receptor agonists have shown neuroprotective effects
in several preclinical studies in AD. Remarkably, they appear to improve almost all
neuropathological features of AD and cognition. In 12-month-old female
APP/PS1/tau AD mice, neurofibrillary tangles, amyloid plaques, and
neuroinflammation in the hippocampus were reduced by lixisenatide. In a rat model
of AD, lixisenatide also prevented Aβ accumulation-induced synaptic damage and
enhanced spatial memory by acting on PI3K-Akt-GSK3β. Exenatide GLP-1RA
(20 µg/kg/day, ip for 2 weeks) reduced neuroinflammation by suppressing TNF-α
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levels in rats. In addition, it improved memory and prevented the loss of hippocampal
neurons.
4-week treatment with exendin-4 was found to reverse memory impairment
in APP/PS1 mice by suppressing aberrant expression of Nacetylglucosaminyltransferase III via the Akt/GSK-3β/β-catenin signaling pathway in
neurons. Levels of N-acetylLH-lucosamine appear to be elevated in the cerebrospinal
fluid of most AD patients, and levels of N — acetylglucosaminyltransferase III, the
glycosyltransferase responsible for the synthesis of the GlcNAc residue, have also
been found to be increased in the brains of AD patients.
Liraglutide (25 nmol/kg, ip, for 2 months) improved spatial memory in a 14month-old APP/PS1 mouse compared to saline treated mice by reducing
inflammation and Aβ production, increasing neuronal progenitor cells in the dentate
gyrus, as well as the number of synapses in the hippocampus and cortex. In another
study, the same authors found that liraglutide may also protect against the progressive
neurodegeneration that develops in AD: in 2-month-old mice, liraglutide (once daily
ip for 8 months) prevented synaptic damage and improved memory. In addition, the
formation of amyloid plaques, inflammation in the cortex was reduced, and
neurogenesis in the dentate gyrus was improved. In contrast, other authors have not
found a beneficial effect of liraglutide in reducing cerebral plaques in APP/PS1
transgenic mice with two distinct clinical mutations of APP/PS1 and AD. In AD
mice, memory deficit was reduced by subcutaneous administration of liraglutide
(25 nmol/day once daily for 8 weeks), which was attributed to a decrease in tau
phosphorylation.
In addition, in APP/PS-1 mice of all ages, chronic administration of liraglutide
promoted neural progenitor cell proliferation, an increase in the number of immature
neurons, and differentiation into mature neurons for the majority of immature cells.
Even in a mouse model of pathological aging that shares neurobehavioral and
neuropathological dysfunction with early sporadic AD, liraglutide increased the
number of CA1 pyramidal neuron in the hippocampus and improved memory.
The effects of GLP-1RA on synaptic defense may include modulation of
neurotrophic factor (BDNF), a trophic factor that promotes differentiation and
survival of neuronal progenitor cells. Indeed, exenatide activates the transcription
factor CREB with an increase in BDNF protein expression, promoting the activation
of the neurotrophic pathway and inhibiting apoptosis in mice with an age-related
cognitive dysfunction model, potentiating long-term memory. Even in mice with AD
(3xTg-BA fed a high-fat diet), exenatide reversed BDNF signaling impairment and
reduced neuroinflammation.
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