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Journal of Alzheimer’s Disease 54 (2016) 445–456
DOI 10.3233/JAD-160284
IOS Press
445
Review
Breakdown of the Cerebrovasculature
and Blood-Brain Barrier: A Mechanistic
Link Between Diabetes Mellitus
and Alzheimer’s Disease
Eric L. Goldwasera,b,1, Nimish K. Acharyad,1, Abhirup Sarkara,b, George Godseya,b
and Robert G. Nagelea,c,∗
aBiomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic
Medicine, Stratford, NJ, USA
bGraduate School of Biomedical Sciences, Rowan University, Stratford, NJ, USA
cDepartment of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford,
NJ, USA
dDepartment of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA
Handling Associate Editor: Thomas Shea
Accepted 12 June 2016
Abstract. Alzheimer’s disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that
afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies
have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research
continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology.
Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke,
have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose
of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of
AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a
link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies
suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown
that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread
connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic
target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be
more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that
is common to both.
Keywords: Alzheimer’s disease, amyloid, blood-brain barrier, dementia, diabetes complications, diabetes mellitus
1These authors contributed equally to this work.
∗Correspondence to: Robert G. Nagele, PhD, Director of Trans-
lational Medicine, New Jersey Institute for Successful Aging,
Rowan University School of Osteopathic Medicine, Stratford, NJ
08084, USA. Tel.:+1 856 566 6083; Fax: +1 856 566 6419; E-mail:
nagelero@rowan.edu.
ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved
446 E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD
INTRODUCTION AND SCOPE
Diabetes mellitus (DM), a metabolic disorder char-
acterized by abnormally high blood glucose levels,
exists as two major types. Type 1 DM is described as
hyperglycemia and insulin deficiency resulting from
immune-mediated destruction of insulin-producing
-cells residing in the islets of Langerhans in
the pancreas. This pathoetiology is responsible for
only 5–10% of the total diabetic population (CDC,
National diabetes fact sheet, 2011). Type 2 DM
is primarily caused by insulin resistance, accounts
for about 90% of DM cases, and more tradition-
ally develops in older individuals. For these reasons,
type 2 DM will be included in the main focus of
this review. Presently, one in eleven Americans has
been diagnosed with DM, while one in three adults
is considered pre-diabetic. On the global scale, 346
million individuals have been diagnosed with DM
and, in 2010, 10.9 million Americans 65 years and
older were diabetic (CDC, National diabetes fact
sheet, 2011). This elderly age group also accounts
for the demographic at risk for Alzheimer’s dis-
ease (AD) (“2012 Alzheimer’s disease facts and
figures,” 2012). Epidemiologic studies hinting at a
close causal connection between DM and AD have
increased dramatically in number according to the
recent literature.
AD is the most prevalent neurodegenerative dis-
ease and the most common cause of dementia in the
elderly. One in nine Americans aged 65 years and
older is diagnosed with AD. Among major leading
causes of death in America, AD is the only chronic
disease with an ever increasing number of fatalities.
The 99.6% failure rate for AD drugs in clinical tri-
als has been both unfortunate and disheartening [1].
In light of this, the field as a whole is in desperate
need of a breakthrough, and serious attention to novel
potential drug targets may provide new opportunities
for successful therapeutic interventions. One promis-
ing and accessible target that has thus far received
little attention is the brain vasculature. A number
of recent studies has suggested a pivotal role for
an impaired blood vasculature in the pathogenesis
of both AD and DM. We conducted a search using
Pubmed indexed articles related to cognitive decline,
and cerebrovascular and blood-brain barrier (BBB)
compromise in diabetic patients, AD patients, and
normal aging. We also scoured the current litera-
ture concerning vascular contributions to dementia in
general, and cognitive-enhancing interventions that
are used for diabetics that may show benefits to the
comorbid AD population. Here, we present some of
the evidence supporting the possibility that an abnor-
mal cerebrovasculature is a common feature of AD
and DM, which may explain why DM is now being
recognized among the most important risk factors for
AD.
EPIDEMIOLOGICAL AND
NEUROPATHOLOGICAL EVIDENCE
SUPPORTS A CLOSE ASSOCIATION
BETWEEN DM, AGING, DEMENTIA,
AND AD
Several studies have demonstrated a greater inci-
dence of cognitive decline in individuals with DM.
Longitudinal studies carried out in Hashimaya, a
small town in Japan, have strongly established DM
as a risk factor for AD [2]. Similar research in the
United States, like the Rotterdam and Rochester stud-
ies, has also pointed to DM as a risk factor for AD
[3, 4]. Individuals diagnosed with DM at an earlier
age have a greater chance of developing AD com-
pared to those who became diabetic at age 65 or
older [5–8]. Similarly, metabolic syndrome, a con-
stellation of metabolic conditions that heighten the
risk for stroke, coronary artery diseases, and type
2 DM, also increases the prevalence of AD [5, 9].
Moreover, a five-year prospective study carried out
by Yaffe and colleagues has revealed an increased
incidence of cognitive decline in individuals with
metabolic syndrome [9].
A number of neuropathological changes are com-
mon to DM and AD. A state of chronic hyperglycemia
in DM patients can result in glycosylation of vari-
ous receptors, leading to the formation of “receptors
for advanced glycation end products” (RAGE) [10].
Several studies have reported an affinity between
amyloid-beta (A) peptides and RAGE, an interac-
tion that has been purported to trigger and propagate
chronic brain inflammation [10, 11]. Higher levels of
RAGE in neurons populating AD brains further bol-
ster a causal role for RAGE in AD pathology [11].
DM and AD are also often recognized as comorbid
diseases since pathological changes such as hyper-
insulinemia, glucose intolerance, hyperglycemia,
insulin resistance, atherosclerosis, hypertension, and
adiposity are common in afflicted patients [5,
12–14]. Aging, hypercholesterolemia, inflammation,
and obesity are additional risk factors associated with
both AD and DM [5, 12–15].
E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD 447
AN ABNORMAL
CEREBROVASCULATURE IS COMMON
IN DM AND DEMENTIAS
Cerebrovascular disease is a general term most
often used to describe the consequences of an
unhealthy and abnormally functioning brain vascula-
ture. As the largest and most evolutionarily advanced
part of the human brain, the cerebral cortex requires
a profuse and steady supply of blood for normal
functioning. Blood vessels of different kinds and
sizes (structural hierarchies) are available to meet
this demand. Normally, during the transit of blood
through the brain vasculature, what leaves the blood
and enters into the brain parenchyma is stringently
regulated by the BBB, with a relatively small subset
of biomolecules being exchanged between brain cells
and blood via specialized receptors and transporters.
This helps to regulate and maintain overall brain
homeostasis as well as electrochemical balances that
are crucial for normal functioning of neuronal cir-
cuitry. Failure to properly control or regulate this
exchange, as in instances of local vascular inflam-
mation, atherosclerosis, hemorrhages, or infarctions
can lead to an indiscriminant leakage of blood compo-
nents, including a diverse array of proteins, metabolic
byproducts, and sometimes pathogens, into the brain
tissue [16].
It is not surprising that vascular abnormalities are
more readily detectable when they involve larger
blood vessels, as they can be more readily visual-
ized by currently available neuroimaging techniques,
such as computed tomography (CT) and magnetic
resonance imaging (MRI). Using MRI, increased
deep white matter lesions, cerebral atrophy, sub-
cortical brain atrophy, white matter hyperintensities,
hippocampal and amygdalar atrophy, and lacunar
infarctions have been found to be more prevalent in
type 2 DM patients compared to controls [17]. The
extent of damage and specific brain regions where
these changes occur dictates the nature of the symp-
tomatology. Acute and extensive leakage of blood
components can be detected using MRI and CT.
Cognitive decline with clear evidence of vascular
compromise has been named vascular dementia, vas-
cular cognitive impairment, or the vascular disease
(VaD) subtype of neurocognitive disorders. However,
currently employed neuroimaging techniques fail to
detect subacute or subclinical lesions/leakages with
reliable and reproducible accuracy [18–20]. We pro-
pose that vascular compromise of the smaller blood
vessels that comprise the microvasculature, such as
arterioles, is chronic and prevalent in AD patients,
while that of larger blood vessels has been linked to
VaD. The latter may present acutely or in a stepwise
degenerative manner as additional individual tribu-
taries become involvedthat service larger segments of
brain tissue. Unfortunately, because the smaller blood
vessels associated with AD are generally beyond the
limits of resolution for commonly used neuroimag-
ing devices, the causal role of a compromised or
dysfunctional cerebrovasculature in AD pathogene-
sis and its progression is more difficult to demonstrate
directly, and thus is constantly being challenged
[20].
As in other parts of the body, capillaries in the
brain exchange oxygen and nutrients for waste and
carbon dioxide. These tiny vessels have a relatively
simple architecture in that they lack the rather elabo-
rate organization of circumferential tunics composed
of smooth muscle layers and connective tissue, other-
wise typical of larger arterioles, venules, and all other
blood vessels greater in size. Instead, capillaries are
lined by a monolayer of vascular endothelial cells that
serves as a physical barrier between the blood and the
brain known as the BBB. Continuous tight junctions
that form between adjacent brain vascular endothelial
cells are the main structural correlate of this barrier. A
number of tight junction proteins, including claudin -
5, -3, and -12, occludin, zonula occludens (ZO) -1 and
-2, and Vascular Endothelial-Cadherin, are known
to be involved in their assembly and maintenance.
Pericytes, astrocytic foot processes, and endothelial
cell basement membranes also appear to support the
structure and function of the BBB, although the exact
nature of their individual contributions to the barrier
functions are unknown and currently under investi-
gation. Along with neurons, this complex is often
referred to as the neurovascular unit, which is cur-
rently depicted as a functional entity that conveys
information between the vasculature and the neurons
that it supports. Further structural details of the BBB
fall outside the scope of this review, but can be found
in a number of excellent articles [21, 22].
THE BBB MAINTAINS NEURONAL
HOMEOSTASIS
As blood vessels penetrate into deeper brain
structures, they progressively decrease in diameter
and eventually feed into a capillary plexus that is
responsible for nourishing a given volume of brain tis-
448 E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD
sue. At this level of proximity to neurons, proper BBB
functionality is crucial for maintaining an optimal
electrochemical milieu and neuronal microenviron-
ment. Failure to have such an effective segregation
of the blood from the neuronal parenchyma can
have devastating results. The BBB is tasked with
carefully regulating which blood components enter
into the immunoprivileged brain tissue [23, 24]. As
in AD, there is a rapidly growing body of evi-
dence implicating a dysfunctional BBB as being
responsible, at least in part, for initiating and/or
propagating many conditions, including epilepsy,
multiple sclerosis, Parkinson’s disease, depression,
and schizophrenia [25–28]. This makes it reason-
able to implicate BBB breakdown as a common
mechanistic link in the initiation and progression of
many, if not all, common neurocognitive disorders,
with the nature of the symptoms being dictated by
the exact brain location and severity of the BBB
compromise.
INCREASED BBB PERMEABILITY IN
DIABETIC PATIENTS AND ANIMAL
MODELS
Several studies have reported increased BBB
permeability in diabetic patients. Starr and col-
leagues used gadolinium and MRI to show significant
increases in BBB permeability in type 2 DM patients
compared to age-matched controls [29]. They also
reported significantly increased BBB permeability in
deeper brain regions (basal ganglia), more so than in
the superficial areas (cortex), but other brain regions
failed to show similar changes in these diabetic sub-
jects.
In streptozotocin-induced diabetic rats, Huber and
colleagues observed an increased BBB permeability
for smaller molecules (e.g., sucrose, 342Da) com-
pared to somewhat larger molecules (e.g., inulin,
5000Da) [30]. The observed increase in BBB per-
meability was region- specific, with the midbrain
exhibiting the greatest extent of BBB compro-
mise. Furthermore, levels of BBB permeability
increased directly with time after induction of dia-
betes. They also reported that insulin treatment was
effective in curtailing BBB compromise, especially
at earlier stages of DM. In another study, BBB
functional integrity was diminished in streptozotocin-
treated diabetic rats [31]. Interestingly, this increased
BBB permeability was coincident with lowered
expression of occludin and ZO-1 proteins. Upon
receiving insulin treatment, hyperglycemia and BBB
permeability were successfully attenuated. These
streptozotocin-treated rats also showed increased
matrix metalloproteinase activity in their plasma.
Altered matrix metalloproteinase activity has been
reported in various neurodegenerative diseases such
as AD and epilepsy [32–34].
EARLIER STUDIES DEMONSTRATING
A DEFECTIVE BBB IN AD PATIENTS
A large number of studies have reported a com-
promised BBB in AD patients. Earlier human studies
have measured and used the levels of certain plasma
proteins normally absent in cerebrospinal fluid (CSF)
as markers of BBB breach. Serum albumin and
immunoglobulin (Ig) G are the two most widely
used plasma protein markers for this purpose. More
recently, Chalbot and colleagues have suggested
the use of secretory Ca2+-dependent phospholipase
A2(sPLA2) activity as a more sensitive marker of
BBB compromise than CSF albumin levels [35].
Levels of sPLA2in AD patients were found to
increase in association with BBB compromise as
compared to controls, suggesting its potential util-
ity as a biomarker. Increased levels of albumin in the
CSF of AD and multi-infarct dementia (a subtype of
VaD) patients compared to controls have also been
reported [36]. Similarly, increased CSF/serum IgG
and albumin ratios (which compares albumin levels
in the blood and CSF) have been shown in both ambu-
latory and institutionalized AD patients [37]. Also
supporting this notion is the higher mean albumin
ratios in the AD group, and overall reduced levels
of serum albumin and IgG in patients with major
depression and early- and late-onset AD [37, 38].
Furthermore, there are significantly higher levels of
serum albumin in late-onset AD or major depres-
sive patients compared to early-onset AD [38]. Along
these same lines, significantly elevated levels of CSF
albumin and albumin quotients were exhibited in the
AD cohort compared to controls [39]. In a three-year
longitudinal study performed on 65 individuals at 85
years of age, there was an increased mean CSF/serum
albumin ratio in the patients diagnosed with AD
and dementia compared to controls [40]. From the
same study, three of the women who later developed
dementia had an increased CSF/serum albumin ratio
compared to those who did not go on to develop
E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD 449
dementia, again signifying this measurement’s util-
ity in even pre-symptomatic diagnostic assays
[40].
These in vivo reports have been further supported
by histopathological studies carried out on post-
mortem AD brains. As in animal studies, the presence
of blood components in the brain parenchyma that
are normally absent are commonly used as indica-
tors of BBB compromise, with IgG and albumin
leakage being the two most widely used for this
purpose. Wisniewski and Kozlowski first reported
extensive perivascular leakage of IgG and albumin
in AD brain samples compared to controls [41].
In agreement with these early reports, additional
work revealed an increased prevalence of micro- or
mini-bleeds, a type of cerebrovascular lesion, in AD
brains compared to controls [42]. Neuroradiological
modalities employed gadolinium-diethylenetriamine
pentaacetic acid (Gd-DTPA) and MRI to demon-
strate the presence of a compromised BBB even at
an early stage of AD [20]. In this study, however,
they failed to demonstrate any significant difference
in the extent of BBB compromise between AD and
age-matched controls. Given the recent understand-
ing that AD pathology can be ongoing decades before
symptoms manifest and the disease is diagnosed,
this finding is not surprising. The ability to accu-
rately establish a “pathologically controlled” non-AD
cohort, rather than a “symptomatically controlled”
non-AD cohort, will be crucial to proper interpreta-
tion of these findings. Unfortunately, at present, it is
impossible to detect accruing AD pathology early on
in the disease development in vivo, even though such
findings are readily uncovered on postmortem brain
tissue.
Our group has also investigated the integrity
of the BBB in age-matched non-demented control
and AD brains by utilizing the direct detection of
extravasation of plasma components such as IgG,
complement protein C1q, and Apeptides as tissue
indicators of BBB breach [43, 44]. AD brains demon-
strated increased incidence of focal BBB compromise
in the cerebral cortex and hippocampus compared
to age-matched controls [43, 44]. Additionally,
in agreement with the earlier findings of Wis-
niewski and Kozlowski, we also commonly observed
regions of BBB compromise in age-matched con-
trol brains [41, 44]. Furthermore, our group and
others have reported increased cerebral amyloid
angiopathy in AD, with the implicated blood ves-
sels exhibiting a greater extent of perivascular leakage
[41, 42, 45, 46].
THE CONCEPT OF A PATHOGENIC
CONNECTION BETWEEN A LEAKY
BRAIN VASCULATURE AND THE
INITIATION AND PROGRESSION OF AD
REMAINS CONTENTIOUS
Contrary to the aforementioned studies and
reports, there are also several studies that have failed
to observe any significant differences in the extent
of BBB permeability between AD and age-matched
controls [47–51]. Skepticism on the causal role of an
abnormal BBB in AD pathogenesis has been widely
cited, as some neuroimaging studies using CT and
MRI have failed to detect evidence of BBB com-
promise [20, 52–54]. More recently, using advanced
dynamic contrast-enhanced MRI, Montagne and col-
leagues were able to demonstrate the accelerated rate
of BBB compromise in the hippocampus of patients
with mild cognitive impairment, a well-recognized
early stage of AD pathology [55]. However, the
understanding that AD pathology begins to develop
decades prior to the emergence of symptoms chal-
lenges the concept of who may serve as appropriate
controls, as mentioned previously [56]. Considering
that up to 50% of individuals over the age of 85 have
symptomatic AD, it is likely that a large proportion
of those not exhibiting symptoms at this age actu-
ally have ongoing pathology, but as yet at a level
insufficient to lead to clear-cut AD-related symptoms
[20].
POPULAR RODENT MODELS OF AD ARE
INADEQUATE FOR STUDYING
VASCULAR CHANGES AND EARLY
STAGES OF AD PATHOLOGY
Over 100 rodent models are available for studies
on AD (http://www.alzforum.org/research-models).
Each of these models were developed for the purpose
of studying one or more aspects of AD-associated
neurodegenerative changes or pathological features
of the disease, such as amyloid plaques, neurofibril-
lary tangles, reactive gliosis, neuronal loss, synaptic
loss, long-term depression/long-term potentiation,
and cognitive decline. Unfortunately, these animals
do not live long enough to develop the same types
of aging-associated changes in the brain vascula-
ture that afflict humans, including BBB breakdown,
and therefore do not naturally develop AD-associated
pathologies within their relatively short lifespan.
Using radiotracers and endogenous mouse IgG
450 E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD
leakage as markers of BBB compromise, vascular
integrity and BBB function were tested in six of the
most commonly used rodent models of AD [57]. Dur-
ing this study, the authors failed to observe significant
incidence of BBB breach in these mouse models com-
pared to the controls.
It is generally thought that symptoms associated
with AD emerge after many years of progressive
neurodegeneration. The best hope for being able to
effectively treat this disease almost certainly lies in
early detection and intervention. The implementation
of early treatments, in turn, will depend on early diag-
noses as well as our ability to definitively identify
causal factors that drive the early stages of disease
initiation. Based on the translational studies carried
out by our group and others, cerebrovascular break-
down appears to be one of the common early triggers
of AD that is rarely considered while designing ani-
mal models to recapitulate human pathology. Instead,
the most widely used animal models of AD involve
forced neuronal overexpression of mutant genes that
does not occur during typical disease pathogenesis in
humans. This provides a possible explanation for the
observation that most AD models fail to show BBB
leak [57]. One must also consider that the structural
hierarchy of affected vessels exhibiting BBB compro-
mise seen in the much larger human brain is virtually
absent in the mouse brain.
To test the effects of BBB and cerebrovascula-
ture compromise on the development of AD-relevant
pathology, we have studied acute [43] and chronic
(manuscript submitted) mouse models. In both acute
and chronic states of BBB compromise, we have
observed significantly elevated levels of extravasated
plasma proteins in the mouse brain parenchyma.
In both models, fluorescein isothiocyanate-labeled
A42 was injected in the general circulation and
found to enter into the brain parenchyma, bind selec-
tively to hippocampal neurons and cortical pyramidal
neurons, and accumulate in the lysosomal compart-
ment of these cells (which are the same cells that
are particularly vulnerable to early stages of AD
pathology) [58]. Additionally, the mouse model with
chronic (i.e., three-month) BBB breach maintained
by repeated injections of Pertussis toxin also demon-
strated hippocampal astrogliosis and a decline in
long-term memory. These rodent models, however,
failed to demonstrate features typical of the termi-
nal stages of AD pathology such as senile plaques,
tangles, and neuronal loss that otherwise accompany
the clinical presentation. In view of the fact that AD
pathology can be underway in humans for a decade
or more before symptoms become apparent and the
disease is considered to be at an early stage, these
findings suggest that mouse models may only be suf-
ficient to represent the very earliest stages of disease
progression, despite clinical correlates in cognitive
tests performed. It is noteworthy to point out that
the pathological changes resulting from acute and
chronic BBB compromise in the rodent target the
same brain regions and closely resemble the changes
seen in human brains at early disease stages.
A PORCINE MODEL IS BETTER SUITED
TO MIMIC HUMAN AD, AND
ESTABLISHES A LINK BETWEEN DM,
BBB COMPROMISE, AND THE ONSET OF
AD-RELATED PATHOLOGY
In a recent study, we investigated the question of
whether or not chronic BBB compromise could lead
to pathological changes consistent with early-stage
AD using a pig model of DM and hypercholes-
terolemia (HC) [59]. This animal model was orig-
inally developed to investigate the pathogenesis of
atherosclerosis in the great vessels, but was subse-
quently found to also increase BBB permeability, thus
enabling relatively long-term studies of the effects of
chronic BBB breakdown on the brain [59]. HC is
often comorbid in humans with DM and also serves
as its own independent risk factor for developing
AD and VaD [5, 10, 13, 14, 60–63]. An associa-
tion between HC and cognitive decline has also been
strongly supported by epidemiological, neuropatho-
logical, and animal studies [63, 64]. It was even
possible to increase the number and size of amy-
loid plaques by feeding a cholesterol-rich diet to AD
transgenic mice [65].
Histopathological analyses of DMHC porcine
brains revealed an increased incidence of BBB breach
as visualized by a significantly higher level of free
IgG present in the brain parenchyma compared to
controls [59]. The extravasation of IgG occurred
primarily in arterioles, with little evidence of signif-
icant leaks from venules or capillaries. Interestingly,
extravasated IgG was also found to selectively tar-
get the surfaces of pyramidal neurons resident in
the cerebral cortex. Along with IgG leakage signif-
icant for AD-like pathology, the DMHC pigs also
exhibited a greater density of A42-positive neurons
compared to controls [59]. Most importantly, pyrami-
dal neurons accumulating A42 also demonstrated
IgG co-labeling, perhaps alluding to a common
E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD 451
mechanistic underpinning shared by these two
events. An “antibody-mediated internalization” phe-
nomenon of A42 is the current focus of a novel
mechanism proposed and investigated for the patho-
genesis of AD [44]. In addition, the vasculature in the
DMHC pigs revealed increased instances of cerebral
amyloid angiopathy and “corkscrew dendrites” in
association with pyramidal cells, two key histopatho-
logical hallmark features of AD brains [44, 59].
CURTAILING VASCULAR
INFLAMMATION THAT FAVORS BBB
COMPROMISE SHOULD BE A MAJOR
THERAPEUTIC TARGET
An important outcome of the above-mentioned
DMHC porcine study was in revealing the benefi-
cial effects of darapladib, a potent anti-inflammatory
inhibitor of lipoprotein-associated phospholipase A2
developed by GlaxoSmithKline, on BBB func-
tional integrity [66]. Treatment of DMHC pigs
with darapladib resulted in a reduction of AD-
associated pathological hallmarks described above,
and included a diminution of IgG leakage from blood
vessels and a decreased number of amyloid-burdened
pyramidal neurons compared to untreated DMHC
controls [66]. Essentially, darapladib successfully
rescued the DMHC animals from the AD pheno-
type that was otherwise observed in untreated DMHC
controls, and restored the pathological indices that
measured back to nearly non-DMHC control lev-
els. By inhibiting the BBB breakdown, this drug
contributed to the maintenance of the proper corti-
cal microenvironment in DMHC pigs. This suggests
that darapladib and other drugs that promote BBB
integrity may have similar utility in both diabetic
and non-diabetic humans, and may also reduce the
incidence and magnitude of the neurodegenerative
changes triggered by chronic DMHC.
These outcomes are also in agreement with pre-
vious studies that implicate abnormalities in the
cerebrovasculature in the pathogenesis of AD and
VaD. Furthermore, we have recently found that
the efficacy of darapladib in inhibiting vascular
anomalies rooted in inflammation may also extend
its beneficial effects to another common afflic-
tion of the diabetic population—diabetic retinopathy
(manuscript submitted). Here, key pathological fea-
tures of diabetic retinopathy, such as edematous
plexiform layers and shrinkage of various cellular
layers, were evident in the same DMHC porcine
model. M¨
uller cell activation also alluded toward the
pathological state and incurred cellular damage. We
have shown increased blood-retinal barrier perme-
ability, as evidenced by selective binding of IgG to
ganglion cells of the retina, which closely resembled
the situation where pyramidal cells in the cerebral
cortex displayed IgG-positivity within or near regions
of BBB breach. As in the cerebral cortex, pathologi-
cal changes observed in the retinal layers of DMHC
pigs were ameliorated by darapladib to near control
levels in the cohort of DMHC pigs. This finding lends
further credence to the concept that chronic inflam-
matory changes in the walls of blood vessels within
the brain can trigger BBB breakdown, initiating a
cascade of pathological events that can culminate in
AD and perhaps other neurodegenerative diseases. It
also suggests that darapladib and other agents that
can block vascular inflammation should be inves-
tigated and evaluated for their capacity to assuage
the rampant neurodegeneration accompanying these
diseases. In fact, rilapladib, a structurally related
compound to that of darapladib with similar pharma-
cokinetic and pharmacodynamic profiles, efficacies,
and tolerances across all age brackets, was studied
in a Phase II clinical trial for early AD. Here, the
researchers, using cognitive tests and biochemical
assays, detected significant benefits for rilapladib-
treated patients to that of placebo [67–69].
ANTI-DIABETIC DRUGS AND OTHER
THERAPEUTIC EFFORTS TARGETING
THE VASCULATURE
It is natural to progress from the mechanistic
underpinnings shared by AD and DM to potential
for overlap in therapeutic interventions (medical or
behavioral). Statins are an obvious choice consider-
ing its many years in use and post-marketing statistics
gathered. A research group in Taiwan followed
elderly DM patients for nearly a decade after starting
statin therapies and found a decrease in the incidence
of AD in those taking statin therapy for DM than in
those not on a statin therapy [70]. Meanwhile, another
study found that although statin use decreased lipid
levels in patients already diagnosed with AD, their
cognitive scores did not improve [71]. The finding
that these therapies are largely ineffective in patients
that have been already diagnosed with AD is not
surprising since we now know that a considerable
amount of AD-related pathology and neuronal death
has already occurred in these individuals prior to
452 E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD
Fig. 1. Diabetes induces blood-brain barrier (BBB) breakdown, triggering Alzheimer’s disease (AD) and perhaps other neurodegenerative
disease. Many complications of diabetes mellitus (DM) are related to a globally impaired vascular integrity, spanning vessel hierarchy and
structure from large to small, and resulting in conditions such as peripheral neuropathy, retinopathy, nephropathy, and coronary artery disease.
These vascular abnormalities extend throughout the body, and include the supply to the cortical and deep brain structures. Here, macrovascular
lesions of the arterial blood supply result in stroke and vascular dementia (VaD). On the other hand, chronic leakage of plasma components
from the microvasculature occurs at the level of arterioles and capillaries as a result of BBB breakdown and contributes to the pathogenesis
and development of AD. Following BBB breakdown, various plasma components, including Ig species (IgG) and amyloid peptides (e.g.,
A42), leak out of the blood vessels, enter into the brain tissue, and bind to pyramidal neurons in regions of vascular compromise. Chronic
BBB leakage drives the binding of Ig and Ato neuronal surfaces, followed by their internalization and accumulation within these cells,
leading to neuronal damage, synaptic loss, cell death, and the appearance of plaques and tangles as pathological hallmarks commonly
observed at autopsy. DM, diabetes mellitus; AD, Alzheimer’s disease; BBB, blood-brain barrier; Ig, immunoglobulin; A42 , amyloid-1−42;
VaD, vascular dementia.
E.L. Goldwaser et al. / Diabetes Disrupts the BBB Leading to AD 453
symptom manifestation and treatment initiation. This
is the most likely explanation for the unfortunately
high failure rate of AD clinical trials. Naturally, as
the disease progresses, a greater volume of the brain
parenchyma is afflicted, which underscores why such
failures have been met with clinical trials for patients
already diagnosed with AD. Recent literature sug-
gests that statin use may be effective in delaying the
onset of AD and slowing the progression from mild
cognitive impairment to AD, but only if treatment
begins prior to overt AD. Pro-inflammatory media-
tors are implicated in many studies linking aberrant
and exaggerated inflammatory processes to AD [72].
Along those lines, pro-resolving mediators, includ-
ing lipoxin A4,may play a key anti-inflammatory
role that can reduce AD symptoms and even promote
amyloid phagocytosis by microglial cells [73, 74].
On the other hand, insulin administered intranasally
showed efficacy in mild cognitive impairment and
early AD patients leading to improved cognition
[75, 76]. Aerobic exercise was demonstrated in an
established mouse model to delay the onset and pro-
gression of AD [77, 78]. Furthermore, behavioral,
diet, and lifestyle modifications are strongly advo-
cated as the best non-pharmacological methods to
prevent the onset and progression AD [79].
CONCLUSION AND PERSPECTIVES
AD and DM are two disorders of growing con-
cern in the US for a multitude of reasons. Given
the alarming rate at which AD is being diagnosed in
the diabetic population, along with a startlingly high
failure rate of AD drugs, it may be time to recon-
sider prevailing models of the pathogenesis of AD.
To more fully understand the mechanisms underly-
ing AD pathology, it is time to devote considerable
attention to the role of the blood vasculature, and
promote research designed to curtail the kinds of vas-
cular pathology that contribute to the disease with the
goal of restoring BBB functionality. We propose that
an early stage in the pathogenesis of AD, preceding
the formation of amyloid plaques, is a compromised
brain microvasculature that includes breakdown of
the BBB. In DM patients, it is suggested that this BBB
compromise arises from the chronic vascular inflam-
mation that also predisposes individuals to dementia
(Fig. 1). This may evolve into a decades-long pre-
symptomatic phase of AD, during which patients are
continuously accruing brain pathology. Here, brain
neurons are metabolically taxed and homeostatically
perturbed by the chronic influx of plasma components
into the brain, but individuals remain asymptomatic.
This early stage of disease presents a prime window
of opportunity to achieve an effective and lasting ther-
apy before extensive brain devastation has occurred.
Toward this end, early treatment with drugs that block
vascular inflammation would be of great benefit, as
they would act to maintain or repair BBB integrity.
Revitalization of a functional BBB would be expected
to help restore brain homeostasis, promote neuronal
health and function, and shed light on a pathoetiol-
ogy that may prove to span multiple neurological and
neurodegenerative diseases.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://j-alz.
com/manuscript-disclosures/16-0284r1).
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