Impaired Cerebral Autoregulation-A Common Neurovascular Pathway in Diabetes may Play a Critical Role in Diabetes-Related Alzheimer’s Disease
Authored by
Fan Fan
Abstract
Alzheimer’s disease (AD) is the leading cause of
progressive degenerative dementia. The hallmark pathological features
include beta amyloid deposition and neurofibrillary tangles. There has
been astrong association of AD with Diabetes (DM) based on human studies
and animal experiments. The hallmark features of AD seem to have an
exaggerated presence in AD with DM, especially type 2 diabetes (T2D). In
addition, insulin resistance is a common feature in both diseases and
as such AD has been called type 3 diabetes. Furthermore, impairment of
cerebral autoregulation has been reported in both animal and human
diabetic subjects. Cerebral vascular impairment has also been implicated
in the pathophysiology of AD. There is an urgent need to develop animal
models of AD and DM to explore the neuropathological mechanisms of
these disease and utilize such models to develop treatment strategies.
AbbreviationsAD: Alzheimer’s Disease; DM: Diabetes; T2D: Type 2 diabetes; Aβ: Amyloid Beta; VSMC: Vascular Smooth Muscle Cells; CO2: Carbon Dioxide; ARIC-NCS: Atherosclerosis Risk in Communities-Neurocognitive Study; BBB: Blood Brain Barrier; APP: Amyloid Precursor Protein; MCA: Middle Cerebral Artery
Introduction
Alzheimer’s disease (AD) and diabetes (DM) are two of
the leading ageing related disorders. AD prevalence accounts for an
estimated 5.4 million Americans in 2016 [1], where as DM affects more
than 29 million Americans in 2013 [2]. AD is the only leading cause of
death (6th overall) [3] that lacks any therapy to slow or reverse its
progression [4] followed by DM as the 7th leading cause of death in
United States (US). The Medicare cost for the treatment of dementia and
AD is $159 billion annually and is projected to rise to $511 billion by
2040 [5,6]. Similarly, DM prevalence is projected to triple by 2050
which costed the nation $245 billion per year in 2012 [2]. These
untreatable chronic disorders will become a major economic
burden long term.Thus, there is an urgent need to understand
the mechanisms of these diseases in order to develop new therapeutic
strategies that delay their progression.
Overall, we confirm the results presented on acute
pancreatitis risk with DPP-4 inhibitors [10] and extend these
findings to GLP-1 receptor agonists (lixisenatide, liraglutide, and
semaglutide). Major alterations of the risk for acute pancteatitis
or pancreatic cancer are not obvious from our analysis, with the
exception of a slightly elevated risk for acute pancreatitis with DPP-4 inhibiutors as previously reported by Tkaz et al. [11].
Interestingly, the present analysis is slightly at variance with a
previous analysis based on phase 3 trials with the same drugs,
coming to the conclusion that, most likely, there is some elevation
in risk for GLP-1 receptor agonists, but not for DPP-4 inhibitors
[12]. We do not suggest the results regarding pancreatic cancer
to indicate that this is proof for a protective effect (although
formally, the estimates would support such conclusion). Rather,
we suggest to take this as evidence against previous estimates
of that risk [2,3]. The methods underlying these conclusions
have been heavily criticised [13], but until now, no competing
data have been available that would allow to derive independent
analyses and conclusions based on state-of-the art methodology.
The recent report of trials aiming at long-term exposure to
incretin-based medications, as a by-product of cardio-vascular
data, the primary motivation and endpoint, has yielded valuable
information that is highly reassuring with respect to a potentially
elevated cancer risk as a consequence of stimulating GLP-1
receptors.This, together with the proven benefits regarding
cardiovascular outcomes reported for liraglutide [9] and
semaglutide [14], will be important determinants of the present
benefit-risk estimation for incretin-based medications.
Introduction
High comorbidity of DM and AD
AD is one of the most common forms of progressive
degenerative brain disorders resulting in dementia [7,8]. AD is
characterized by a decline in short term memory, problem-solving,
complex cognitive skills and later language dysfunction. Loss in ability
to perform everyday activities requires constant nursing and long -term
dependence. This decline occurs because of wide spread cortical
neuronal loss in areas of brain responsible for cognitive function.
Whereas, DM is a variable disorder of carbohydrate metabolism resulting
in hyperglycemia,
which, if persists chronically, can lead to systemic complications
including cognitive impairment T2D, which begins as insulin
resistance and is the most common form of DM. Numerous
studies demonstrate that diabetics are at an increased risk of
developing AD especially in the elderly. As a result, AD has been
proposed as Type 3 DM in appropriate context [9]. Recent animal
studies are proposing an increased association of T2D with AD
[10,11]. This association has also been corroborated in human
epidemiological studies [12,13].
A clear mechanism underlying AD has yet to be fully
understood. Earlier hypotheses of neuro degeneration in AD
relied heavily on cholinergic deficiency, extracellular amyloid
beta (Aβ) plaque formation, and hyperphosphorylated Tau
protein induced neurofibrillary tangles [14]. However, current
treatments and clinical trials targeting these pathways, such as
using inhibitors of acetylcholinesterase [15], and γ secretase
[16-19] or immunotherapy targeting to Aβ and Tau [18], have
not been proved to be able to stop or slow down the disease
process of AD. Lack of effective pharmacological interventions
has led the community to reconsider alternatives [14].There is
increased evidence indicating that cerebral vascular dysfunction
plays an important role in the development of dementia and
AD. A vascular pathogenesis has thus been proposed which
comprises cerebral hypoperfusion, blood-brain barrier (BBB)
dysfunction [14,20,21] and impaired cerebral microcirculation
[22,23]. Diabetics with AD have increased numbers of beta
amyloid plaques, tau-positive cells, advanced glycation end
products and more activated microglia than the brains of AD
patients without diabetes. These effects are markedly seen
in the hippocampus [24]. The proposed mechanisms include
insulin resistance [25], inflammation [26] and impaired glucose
transporters [27]. However, there is additional impairment
in cerebral autoregulation [28] resulting in microinfarction,
hemorrhages, and eventual neuronal loss.
High Cerebral Autoregulation
Cerebral autoregulation was first described by Lassen in
1959, where he reported clinical studies assessing cerebral blood
flow [29]. Since then, cerebral autoregulation has been broadly
used to describe the local circulatory changes as well the global
perfusion related changes in the brain [30]. For this review,
we will use the cerebral autoregulation as blanket definition
which encompasses both mechanoregulation as well chemoregulation.
Perfusion related change occurring in large vessels
has been described else where as mechanoregulation, where as,
vascular changes occurring in response to changes in arterial
CO2 is described as chemoregulation or metabolic regulation
[30,31]. Furthermore, changes occurring locally around neurovascular
junction are referred to as neurovascular coupling
[30]. Cerebral autoregulation is an inherent mechanism where
by the cerebral vasculature maintains constant cerebral blood
flow by responding to systemic changes in blood pressure and thus maintaining neurovascular homeostasis [32-34]. Impaired
cerebral autoregulation has been reported with advancing
ageing [35-37], hypoxemia/ischemia [35] and hyperglycemia
[38], suggesting these conditions are related to dysfunction at
the autoregulatory pathway. Thus, it is important to understand
the pathophysiology of cerebral autoregulation. The vessel’s
ability to autoregulate with rise and drop in blood pressure is
achieved mainly through myogenic response, and additional
enhancement is achieved through metabolic activators [39].
Vascular smooth muscle cells (VSMC) are the main contractile
vascular structures and are predominantly located in the wall of
cerebral arteries as well pial and penetrating arterioles. These
cells respond to pressure elevation by a constriction mechanism
using Bayliss myogenic response [40]. Such response has been
observed [33,34,41] in the middle cerebral artery territory
(MCA) of the rats, where large diameter arteries (202μm)
display greater myogenic response between 60-100 mmHg,
whereas penetrating arterioles (58μm) show greater response
between 20-16mmHg [42]. The myogenic response is enhanced
by vasoconstrictors, e.g. Angiotensin II, ET1, and 20 HETE
[33,43]. In contrast, during drop in blood pressure, vessels dilate
in response to metabolic active vasodilators, e.g. Nitric Oxide
(NO), endothelial derived hyperpolarizing factor, adenosine,
extracellular K+, hydrogen ion, lactate, and carbon monoxide
(CO) [44]. These metabolites are released at the level of
neurovascular couplingfrom endothelial cells, and glial cells [45],
including astrocytes [46], due to hypoxemia (reactive hyperemia)
[47,48] or neuron activation (functional hyperemia) [45,49].
Thus, any dysfunction of these smooth muscles, endothelial
and glial cells could result in autoregulatory dysfunction.
Furthermore, the degree of vascular remodeling also contributes
to the regulation of cerebral mechanoautoregulation. Increased
vascular wall thickness and perivascular fibrosis could affect
vascular compliance and decrease the ability of a blood vessel
wall to expand in response to changes in blood pressure [50,51].
Enhanced vascular remodeling and decreased compliance has
been reported in DM [52,53] as well in AD[54-56].
Cerebral autoregulation, DM and AD
Aging results in impairment of autoregulation which
increases the risk of cerebral pathology including stroke,
vascular cognitive impairment [57-60], and AD [60-62]. The risk
isincreased with coexistence of hypertension and diabetes [63].
With ageing, there is increased rarefaction of small penetrating
arteries to deeper structures of the brain especially the basal
ganglia and periventricular white matter [59,62,64]. This results
in compromised regional blood flow and formation of lacunar
infarctions, as well microbleeds, all of which are correlated with
decline in cognitive function [62,65,66]. As ageing advances,
there is BBB breakdown, vascular remodeling, glial cell activation,
and inflammation further exacerbating the neurodegeneration
[51,58-60,67,68]. Evidence suggests that the myogenic response
of the MCA is impaired in AD [44] and DM [69]. Persistent hyperglycemia is associated with cerebral vascular dysfunction,
BBB leakage, and inflammation that may contribute to the
development of neurodegeneration and eventually dementia.
In AD, there is reduction in number of microvessels, VSMCs and
flattening of endothelial cells [70], suggesting AD may be linked
to impaired cerebral autoregulation. The Atherosclerosis Risk
in Communities-Neurocognitive Study (ARIC-NCS) population,
especially the diabetic population, was noted to have mild
cognitive impairment (the early stage of AD) [12]. Two-hit
hypothesis was first described by Zlokovic, BV. According to this
hypothesis, there are vascular medicated injuries occurring from
DM, Hypertension, and Stroke, which ensue a non-amyloidogenic
pathway resulting in dementia [21]. In DM, arteriosclerosis
occurs due to glycosylation, and as a result, vessels lose the
stretch reflex, transferring the arterial pressure to the capillaries
which in turn results in vascular leakage through breakdown of
the BBB and oligemia (local reduction in blood flow): this last
step is described as first hit [21]. consequently, the breakdown of
BBB results in microinfarction, microbleeds, toxic accumulation
and less clearance of Aβ proteins. Whereas, oligemia leads
to APP expression and increased AB production which result
in excess of Aβ: this step is described as second hit [21]. This
furthers the cascade and thus perpetuates neuronal dysfunction
and injury resulting in cognitive decline, and neurodegeneration
[21,62,65].
Indeed, insulin resistance and glucose transporter
dysfunction in the brain play important roles in T2D related
AD. In a recent cohort study of about 1500 patients with
T2D, researchers treated patients with Metformin vs. other
hypoglycemic agents in order to observe change in cognition. They
found that metformin intervention significantly reduced the risk
of developing dementia by 20% when compared other diabetic
therapies [71]. In another study, the use of sulfonylureas and
metformin over 8 years, resulted in a decreased risk of dementia
by 35% [72]. In addition, the amyloid precursor protein (APP)
gene, which is associated with some cases of AD, has been shown
to be involved in the insulin pathway. Therefore, impairment of
this pathway can result in T2D [73]. On the other hand, impaired
glucose utilization in mice via overexpression APP has been
reported to cause derangement of CBF [74]. Furthermore,
reduced expression of the glucose transporter GLUT1 [75,76]
and GLUT3 [75,77] exacerbates AD, thus exacerbating the risk
of dementia with each severe hypoglycemic episode in elderly
diabetic patients [78-80].
Ideal Animal Models for Future Studies
To further elucidate the common pathology in AD and DM,
there is need for an ideal animal model. A mixed mice model of
T2D and AD has been generated by crossing APP/PS1 mice (AD
model) with db/db mice (T2D model) [81]. This model exhibits
microglia activation, BBB leakage, brain atrophy, and tau
pathology. More recently, our group used a rat T2D model- T2DN, and found that it is associated with impaired autoregulation of
CBF, glial activation, inflammation and Alzheimer-like cognitive
deficits [82,83]. The T2DN rats closely mimic changes in diabetic
patients and develops diabetic nephropathy at 6 months of age
due to impaired renal autoregulation [84-86]. Nevertheless, both
animal models exhibit cerebral vascular dysfunction suggesting
a greater need to explore their common ground of vascular
pathology.
Conclusion
AD and T2D are age dependent diseases. There are several
potential mechanisms that have been proposed to be involved in
the pathogenesis of AD including classical Aβ protein deposition,
tau associated neurofibrillary tangles as well as the acetylcholine
deficiency. Previous generations of treatment focusing on these
mechanisms have failed to prevent the progression of AD, giving
rise to the need for alternative therapeutic approaches. Recent
studies have suggested that insulin resistance and cerebral
autoregulation could be responsible for common pathogenesis in
comorbid AD and DM. It is possible that impaired autoregulation
is occurring very early before the onset of dementia. Whether
this cerebral vascular dysfunction precedes neurodegeneration
or whether it is simply an outcome of amyloid and tau deposition
has yet to be validated. In order to identify this pathology and
even to develop therapeutic interventions there is a great need
for the development of an ideal animal model. The recent data
on mixed T2D and AD mice and T2DN rat models are promising,
however, further research is required to validate whether
these models are ideal for mechanisms involved in “type 3 DM,’
especially starting from the cerebral vascular function aspect.
Acknowledgement
This study was supported by grants AG050049 (FF),
P20GM104357 (FF) from the National Institutes of Health, and
16GRNT31200036 (FF) from the American Heart Association.
The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
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