**2. Type 2 diabetes, vascular changes and Alzheimer's disease**

**Insulin signaling in the vasculature** Activation of the insulin receptor (IR) leads to phos‐ phorylation of insulin receptor substrate (IRS) which serve as docking proteins for phospha‐ tidylinositol 3-kinase (PI3K). PI3K generates phosphatidyl-3,4,5-triphosphate (PIP3) which then phosphorylates 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Finally, PDK-1 phosphorylates Akt and stimulates endothelial nitric oxide synthase (eNOS) resulting in the production of nitric oxide (NO) and vascular relaxation [17, 18]. Interestingly, insulin receptor activation can also mediate vasoconstriction. Activation of IR can also lead to phosphorylation of Shc which then binds Grb-2 resulting in activation of Sos. This complex then activates Ras leading to phosphorylation Raf which results in activation of MAPK. Activation of MAPK stimulates release of endothelin-1 (ET-1), a vasoconstrictor [19-21]. By mediating vascular properties, insulin signaling plays a significant role in glucose and oxygen availability to the brain. Conversely, dysfunction in insulin signaling, as observed in T2DM, has profound detrimental effects on hemodynamics and, thus, maintenance of normative brain function.

**Vascular complications associated with type 2 diabetes** It is estimated that approximately 200 million people worldwide have diabetes and by 2025 the number is expected to increase to 333 million [22]. Epidemiological studies have indicated that patients with T2DM have a greater incidence of cardiovascular disease, cerebrovascular disease (CVD), hypertension and renal disease relative to the general population [8, 9]. In addition, a large number of populationbased studies have identified diabetes as a risk factor for dementia [23-25], primarily as a result of CVD [26, 27]. At only 3% of body weight, the brain uses ~20% of the body's oxygen and ~25% of the body's blood glucose [28, 29], demonstrating that it is by far the most metabolically active organ. This oxygen and glucose consumption is constantly required, since brain neurons are obligate aerobic cells and have no other source of energy. The majority of this energy is used to maintain cellular ionic homeostasis, and thus when cerebral blood flow (CBF) ceases, brain function ends within seconds and damage to neurons occurs within minutes [30].

Other factors that contribute to AD such as insulin resistance and accumulation of the neurotoxic peptide amyloid beta (Aβ) are also examined. It's likely that no central cause of AD exists but rather, the disease represents a breakdown of several critical components involved

**Epidemiology of AD and T2DM** AD is the most common form of dementia [2] and remains incurable. While the cause of AD remains unknown, several risk factors have been identified

T2DM is a known risk factor for AD [1] suggesting that insulin signaling abnormalities play a central role in AD pathology. Moreover, AD brains show decreased insulin levels, decreased activity of insulin receptors and signs of compensatory mechanisms such as increased insulin

Loss of insulin signaling in diabetes can occur by either type 1 or type 2 processes. Type 1 diabetes mellitus (T1DM) is characterized as an autoimmune disease that results in the destruction of insulin producing β cells found in the pancreas. In contrast, T2DM is a state of insulin resistance in which insulin levels are normal or elevated but tissues are unresponsive to its effects. While both T1DM and T2DM can lead to cognitive deficits, T2DM poses a greater risk for AD development [6, 7] and as a result the parallels between T2DM and AD are studied more vigorously than T1DM associations. Therefore, the majority of information presented

In addition to insulin resistance, T2DM is associated with the development of vascular dysfunction in the brain [8, 9]. T2DM is a risk factor for microvascular complications as well as macrovascular defects [10] such as stroke [11]. Vascular abnormalities are strongly associ‐

**Insulin signaling in the vasculature** Activation of the insulin receptor (IR) leads to phos‐ phorylation of insulin receptor substrate (IRS) which serve as docking proteins for phospha‐ tidylinositol 3-kinase (PI3K). PI3K generates phosphatidyl-3,4,5-triphosphate (PIP3) which then phosphorylates 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Finally, PDK-1 phosphorylates Akt and stimulates endothelial nitric oxide synthase (eNOS) resulting in the production of nitric oxide (NO) and vascular relaxation [17, 18]. Interestingly, insulin receptor activation can also mediate vasoconstriction. Activation of IR can also lead to phosphorylation of Shc which then binds Grb-2 resulting in activation of Sos. This complex then activates Ras leading to phosphorylation Raf which results in activation of MAPK. Activation of MAPK stimulates release of endothelin-1 (ET-1), a vasoconstrictor [19-21]. By mediating vascular properties, insulin signaling plays a significant role in glucose and oxygen availability to the brain. Conversely, dysfunction in insulin signaling, as observed in T2DM, has profound detrimental effects on hemodynamics and, thus, maintenance of normative brain function.

ated with AD [12-16] implying further involvement of T2DM in disease onset.

**2. Type 2 diabetes, vascular changes and Alzheimer's disease**

in the general health and function of the brain.

410 Understanding Alzheimer's Disease

here pertains to type 2 diabetic pathologies.

that may provide insight into the fundamentals of AD pathogenesis.

receptor density [3] indicating AD as "type 3 diabetes" [4, 5].

The vascular complications associated with diabetes can be divided into two classes based on the vascular etiology of their pathology: macrovascular (hypertension, coronary artery disease, atherosclerosis, stroke) and microvascular (neuropathy, retinopathy, nephropathy). Macro‐ vascular complications are those that affect the larger (non-capillary) blood vessels. Statistics show that diabetes increases the risk of stroke and atherosclerosis [31]. Atherosclerosis accounts for 70% of morbidity associated with T2DM [32], while other studies have shown an association between the degree of hyperglycemia and increased risk of myocardial infarction and stroke [33-36]. While macrovascular complications themselves represent important pathological consequences of T2DM, they have also been shown to provide the etiological link between T2DM and the development of Alzheimer's disease.

**Link between type 2 diabetes and Alzheimer's disease** AD is an age-related disorder characterized by progressive cognitive decline and dementia. An estimated 5.3 million people in the United States are currently affected and represents the sixth-leading cause of death. Significant evidence has been provided that links T2DM to AD. For example, a comprehensive meta-analysis showed that the aggregate relative risk of AD for people with diabetes was 1.5 (95%-CI 1.2 to 1.8) [37]. Studies have shown that T2DM, impaired fasting glucose and increased islet amyloid deposition are more common in patients with Alzheimer's disease than in control subjects [38, 39]. Unsurprisingly, insulin signaling provides an important mechanistic link between T2DM and AD.

Ischemic CVD caused by T2DM is positively associated with AD through shared pathological mechanisms such as hyperinsulinemia, impaired insulin signaling, oxidative stress, inflam‐ matory mechanisms and advanced glycation end-products (AGEs) [40]. Defective insulin signaling is associated with decreased cognitive ability and development of dementa, includ‐ ing AD [41], rendering signaling neurons more vulnerable to metabolic stress and accelerating neuronal dysfunction [42]. In vitro insulin-stimulated Akt phosphorylation is decreased in hyperinsulinemic conditions in cortical neurons [43]. Finally, all forms of amyloid beta (Aβ) (monomers, oligomers and Aβ-derived diffusible ligands (ADDLs)) can inhibit insulin signaling by directly binding to the insulin receptor and inhibit insulin signaling [44].

**Mechanisms of macrovascular complications of diabetes** A central pathological mechanism in diabetic-related macrovascular disease is atherosclerosis, which leads to the hardening of arterial walls throughout the body resulting in impaired blood flow. Although the mechanism for the susceptibility of diabetic patients to ischemic heart disease remains unclear, accumu‐ lating lines of evidence implicate hyperglycemia, hyperlipidemia and inflammation as playing key roles in the development of this disorder [45]. This link between obesity and both T2DM and atherosclerosis implicates elevated amounts of glucose oxidized LDL and free fatty acids (FFAs) in disease pathogenesis, potentially as triggers for the production of pro-inflammatory cytokines by macrophages [32].

In the insulin resistant state, there is a specific impairment in the vasodilatory PI3K pathway, whereas the Ras/MAPK-dependent pathway is unaffected [46, 47]. This results in decreased production of NO and an increased secretion of ET-1 in humans [48] leading to increased vasoconstriction. The decrease in NO production is significant in that NO protects blood vessels from endogenous injury by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell prolifer‐ ation and migration [49, 50]. Decreased production of NO allows for increased expression of proinflammatory transcription factor NF-κB, and subsequent expression of leukocyte adhe‐ sion molecules and production of chemokines and cytokines [51]. Activation of these proteins promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, initiating the morphological changes associated with the onset of atherosclerosis [52, 53].

High levels of FFAs are found in insulin-resistant individuals. FFAs generated by increased activity of hormone-sensitive lipase that contribute to and result in insulin resistance [54-56]. In vitro vascular endothelial cell culture treated with FFA resulted in decreased insulinstimulated eNOS activity and NO production [57]. It is believed that FFA increases cellular levels of diacylglycerols, ceramide, and long-chain fatty acyl coenzyme A (CoA), all of which have been shown to activate protein kinase C (PKCβ1). Activation of PKCβ1 results in increased phosphorylation of IRS-1 that leads to reduced Akt and eNOS resulting in decreased vasodilatory capacity [58, 59]. Increase in FFAs result in an increase in reactive oxygen species (ROS) from NADPH and the mitochondrial electron transport chain [60]. The increase in ROS results in increased PKC which activates the hexosamine biosynthetic pathway leading to increased AGEs and subsequent decrease in endothelial-derived NO [60]. Hyperglycemia has been found to decrease activation of Akt and eNOS via O-GlcNAC of eNOS at the Akt phosphorylation sites [61, 62]. Hyperglycemia increases activation of PKCα, PKCβ, PKCδ resulting in decreased eNOS and concomitant increase in endothelial ET-1 [60]. T2DM is associated with vascular dysfunction as a result of increased atherosclerosis and decreased cerebral blood flow. The combination of both processes is decreased glucose and oxygen supply to vital organs such as the brain. The biochemical events leading to the macrovascular impairment has particular significance to brain health as the risk of stroke is a major compli‐ cation of T2DM.

1

Insulin

Vasoconstriction Vasodilation

sclerosis, ultimately leading to macrovascular complications (*3*).

Shc IRS1

NON-DIABETIC

Insulin Receptor

MAPK Akt

ET-1 eNOS

Increased hypoxia-ischemia

Increased oxidative stress Increased ROS production Increased inflammatory response

Vasoconstriction Vasodilation

Shc IRS1

T2DM

FFA

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 413

Hyperglycemia

MAPK Akt

ET-1 eNOS

Macrovascular complications (stroke,CAD)

2

3

**Figure 1.** Pathways leading to macrovascular complications of type 2 diabetes mellitus (T2DM). In non-diabetic indi‐ viduals (*left*), activation of the insulin receptor can result in activation of both vasodilatation and vasoconstriction. Un‐ der normative conditions, there is a balance of both processes to regulate the immediate metabolic requirements of various tissues. In type 2 diabetic patients (*right*), factors such as an increase in free fatty acids and hyperglycemia have been shown to specifically inhibit the Akt pathway while the MAPK pathway remains unaffected. This leads to an im‐ balance in homeostatic regulation of vascular function and hemodynamics (*1*). The resultant decrease in nutrient availability to affected tissues results in an increase in oxidative stress and ROS production and an increased inflamma‐ tory response (*2*). Released pro-inflammatory cytokines and macrophage recruitment instigates the onset of athero‐

Atherosclerosis

**Type 2 diabetes and cardiovascular disease** T2DM has been shown to be associated with an increased risk of coronary heart disease and stroke [63-66]. Insulin resistance, the mechanism underlying T2DM, has also been linked to a higher incidence and recurrence of stroke [67]. Two key pathological mediators of stroke observed in T2DM are intracranial stenosis [68] and

arterial walls throughout the body resulting in impaired blood flow. Although the mechanism for the susceptibility of diabetic patients to ischemic heart disease remains unclear, accumu‐ lating lines of evidence implicate hyperglycemia, hyperlipidemia and inflammation as playing key roles in the development of this disorder [45]. This link between obesity and both T2DM and atherosclerosis implicates elevated amounts of glucose oxidized LDL and free fatty acids (FFAs) in disease pathogenesis, potentially as triggers for the production of pro-inflammatory

In the insulin resistant state, there is a specific impairment in the vasodilatory PI3K pathway, whereas the Ras/MAPK-dependent pathway is unaffected [46, 47]. This results in decreased production of NO and an increased secretion of ET-1 in humans [48] leading to increased vasoconstriction. The decrease in NO production is significant in that NO protects blood vessels from endogenous injury by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell prolifer‐ ation and migration [49, 50]. Decreased production of NO allows for increased expression of proinflammatory transcription factor NF-κB, and subsequent expression of leukocyte adhe‐ sion molecules and production of chemokines and cytokines [51]. Activation of these proteins promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, initiating the morphological changes associated with the onset of

High levels of FFAs are found in insulin-resistant individuals. FFAs generated by increased activity of hormone-sensitive lipase that contribute to and result in insulin resistance [54-56]. In vitro vascular endothelial cell culture treated with FFA resulted in decreased insulinstimulated eNOS activity and NO production [57]. It is believed that FFA increases cellular levels of diacylglycerols, ceramide, and long-chain fatty acyl coenzyme A (CoA), all of which have been shown to activate protein kinase C (PKCβ1). Activation of PKCβ1 results in increased phosphorylation of IRS-1 that leads to reduced Akt and eNOS resulting in decreased vasodilatory capacity [58, 59]. Increase in FFAs result in an increase in reactive oxygen species (ROS) from NADPH and the mitochondrial electron transport chain [60]. The increase in ROS results in increased PKC which activates the hexosamine biosynthetic pathway leading to increased AGEs and subsequent decrease in endothelial-derived NO [60]. Hyperglycemia has been found to decrease activation of Akt and eNOS via O-GlcNAC of eNOS at the Akt phosphorylation sites [61, 62]. Hyperglycemia increases activation of PKCα, PKCβ, PKCδ resulting in decreased eNOS and concomitant increase in endothelial ET-1 [60]. T2DM is associated with vascular dysfunction as a result of increased atherosclerosis and decreased cerebral blood flow. The combination of both processes is decreased glucose and oxygen supply to vital organs such as the brain. The biochemical events leading to the macrovascular impairment has particular significance to brain health as the risk of stroke is a major compli‐

**Type 2 diabetes and cardiovascular disease** T2DM has been shown to be associated with an increased risk of coronary heart disease and stroke [63-66]. Insulin resistance, the mechanism underlying T2DM, has also been linked to a higher incidence and recurrence of stroke [67]. Two key pathological mediators of stroke observed in T2DM are intracranial stenosis [68] and

cytokines by macrophages [32].

412 Understanding Alzheimer's Disease

atherosclerosis [52, 53].

cation of T2DM.

**Figure 1.** Pathways leading to macrovascular complications of type 2 diabetes mellitus (T2DM). In non-diabetic indi‐ viduals (*left*), activation of the insulin receptor can result in activation of both vasodilatation and vasoconstriction. Un‐ der normative conditions, there is a balance of both processes to regulate the immediate metabolic requirements of various tissues. In type 2 diabetic patients (*right*), factors such as an increase in free fatty acids and hyperglycemia have been shown to specifically inhibit the Akt pathway while the MAPK pathway remains unaffected. This leads to an im‐ balance in homeostatic regulation of vascular function and hemodynamics (*1*). The resultant decrease in nutrient availability to affected tissues results in an increase in oxidative stress and ROS production and an increased inflamma‐ tory response (*2*). Released pro-inflammatory cytokines and macrophage recruitment instigates the onset of athero‐ sclerosis, ultimately leading to macrovascular complications (*3*).

carotid atherosclerosis [69]. Insulin resistance has been associated with elevated expression of the fibrinolytic inhibitor plasminogen activator inhibitor 1 [70] resulting in decreased fibri‐ noyltic capacity and concurrent increased thrombosis due, in part, to an increase in platelet activation [71]. Insulin resistance has also been shown to induce endothelial dysfunction and inflammation [71], adversely affecting vascular function and initiating atherosclerosis, respectively. Collectively, these data implicate insulin resistance to the impairment of norma‐ tive cerebrovascular function resulting in the activation of pathways that encourage the onset of stroke. Stroke could, in turn, exacerbate and/or initiate the onset of another disorder such as AD.

have revealed extensive degeneration of endothelium [85] and features indicative of BBB breakdown [86]. At the cellular level, AD is known to cause abnormal structural changes to arterioles and capillaries, swelling and increased number of pinocytotic vesciles in endothelial cells, decreased mitochondrial content, increased deposition of proteins of the basement membrane, reduced microvascular density and occasional swelling of astrocyte endfeet [87-92]. Aβ trafficking across the BBB deposition is also dependent on mechanisms of influx and efflux. Increased expression of receptor for advanced glycation endproducts (RAGE) may be responsible for Aβ influx from the blood to the brain has been reported in addition to a decrease in LRP1 receptors that are responsible for clearing Aβ from the brain to the blood [12,

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 415

A functional consequence associated with BBB dysfunction is the resultant impairment in cerebral hemodynamics. AD impairs autoregulation, the mechanism that is responsible for the stabilization of blood flow to the brain in response to changes in cerebral perfusion pressure [94]. In an APP x PS1 mouse model neurovascular coupling, the process in which activation of a brain region evokes a local increase in blood flow, was impaired [95]. Finally, AD has shown to adversely affect vasomotor/vascular reactivity, the process that mediates vasodila‐ tory or vasoconstrictor responses of cerebral blood vessels to hypercapnic or hypocapnic stimuli (ie. global or regional brain blood flow response to systemic changes in arterial CO2) [96-98]. Cumulatively, the impairment of these processes adversely affects cerebral blood regulation that, in turn, would negatively affect nutrient availability to neurons. This would result in cerebral hypoperfusion, a process that is widely believed to initiate the onset of AD

There are a number of known direct links between biochemical pathways central to AD and hypoxia/ischemia. A rat model for vascular cognitive impairment has been devel‐ oped referred to as the two-vessel occlusion model of cerebral ischemia. Studies found decreased cerebral blood flow up to 4 weeks, cognitive deficits, APP proteolysis to form Aβ-sized fragments [99-101]. Other studies have observed an overexpression of Aβ per‐ sisting for up to 3 months after surgery [102] and cognitive impairment [103], strongly suggesting that decreased CBF is a key mediator in the pathophysiology of AD. Several studies have been able to identify some of the molecular mechanisms as to how hypoxia/

APP expression increases following chronic cerebral hypoperfusion and ischemia [104, 105], and a greater proportion of APP is proteolytically cleaved by increased activity of amyloido‐ genic enzyme, BACE1, which is concurrently increased in AD following ischemic events [106]. Hypoxia inducible factor-1α (HIF-1α) plays an essential role in cellular and systemic responses to low oxygen and has been found to increase BACE1 mRNA expression [107]. Furthermore, BACE1 stabilization is enhanced in AD in addition to a decrease in its trafficking [108, 109]. Increased BACE results in greater γ-secretase-mediated production of Aβ [110]. In an APP overexpressing mouse model, chronic cerebral hypoperfusion as the result of cerebral amyloid angiopathy (pathological deposition of Aβ1-40 in brain blood vessels) was followed by an increased rate of leptomeningeal Aβ precipitating the risk of microinfarcts [111]. Hypoxia/

93].

pathology.

ischemia exerts its effects on AD-related genes.

Pre-existing CVD has been identified as a significant risk factor for AD. The vascular hypoth‐ esis of AD posits that vascular dysfunction, such as stroke, is a pre-requisite for the develop‐ ment of this disorder. It has been reported that the risk of AD is three times greater after the occurrence of stroke [72]. Stroke may result in neurodegeneration [73, 74], resulting in the rapid cognitive decline observed in AD patients [75]. It has even been proposed that stroke may be the underlying cause of 50% of AD cases [74]. Conversely, individuals presenting with severe cognitive impairments, and possibly AD, may be at a greater risk for the development of stroke or CVD [76, 77].

The amyloid hypothesis of AD was long held as the prevailing theory explaining the etiology of AD. However, emerging evidence compiled from the last 20 years has suggested that the pathology associated with AD is vascular in origin. The vascular hypothesis of AD states that pre-existing cardiovascular dysfunction such as stroke, hypertension and atherosclerosis results in chronic cerebral hypoperfusion that could encourage the onset of AD. Several lines of evidence have been provided in support of this hypothesis. For example, it has been shown that cerebrovascular dysfunction precedes cognitive decline and the onset of neurodegenera‐ tive changes in AD and AD animal models [12, 13]. In rhesus monkeys, dystrophic axons labeled with amyloidogenic enzyme, BACE1, were found in close proximity or in direct contact with cortical blood vessels [78], asserting a tight association with AD pathology and vascular dysfunction. Clinical and epidemiological evidence provides further support of the vascular hypothesis.

AD patients show a greater degree of vascular narrowing of carotid arteries [65] and cerebral arteries of the Circle of Willis [79, 80]. In addition, large artery CVD was positively correlated to the frequency of neuritic plaques [81]. Several vascular risk factors such stroke (silent infarcts, transient ischemic attacks), atherosclerosis, hypertension, heart disease (coronary artery disease, atrial fibrillation) and diabetes mellitus have been associated with an increased risk AD-type dementia [82]. Between 60 to 90% of AD patients exhibit various cerebrovascular pathologies including White matter lesions, cerebral amyloid angiopathy (CAA), microin‐ farcts, small infarcts, hemorrhages and microvascular degeneration [12-16]. It believed that cardiovascular dysfunctions act as a nidus for accelerated Aβ deposition resulting in the onset of AD [83].

Aberrant blood brain barrier (BBB) function exposes neurons to neurotoxic substances. Chronic cerebral hypoperfusion is believed to render the brain more vulnerable to various insults, resulting in AD and associated cognitive loss [84]. Clinical observations in AD patients have revealed extensive degeneration of endothelium [85] and features indicative of BBB breakdown [86]. At the cellular level, AD is known to cause abnormal structural changes to arterioles and capillaries, swelling and increased number of pinocytotic vesciles in endothelial cells, decreased mitochondrial content, increased deposition of proteins of the basement membrane, reduced microvascular density and occasional swelling of astrocyte endfeet [87-92]. Aβ trafficking across the BBB deposition is also dependent on mechanisms of influx and efflux. Increased expression of receptor for advanced glycation endproducts (RAGE) may be responsible for Aβ influx from the blood to the brain has been reported in addition to a decrease in LRP1 receptors that are responsible for clearing Aβ from the brain to the blood [12, 93].

carotid atherosclerosis [69]. Insulin resistance has been associated with elevated expression of the fibrinolytic inhibitor plasminogen activator inhibitor 1 [70] resulting in decreased fibri‐ noyltic capacity and concurrent increased thrombosis due, in part, to an increase in platelet activation [71]. Insulin resistance has also been shown to induce endothelial dysfunction and inflammation [71], adversely affecting vascular function and initiating atherosclerosis, respectively. Collectively, these data implicate insulin resistance to the impairment of norma‐ tive cerebrovascular function resulting in the activation of pathways that encourage the onset of stroke. Stroke could, in turn, exacerbate and/or initiate the onset of another disorder such

Pre-existing CVD has been identified as a significant risk factor for AD. The vascular hypoth‐ esis of AD posits that vascular dysfunction, such as stroke, is a pre-requisite for the develop‐ ment of this disorder. It has been reported that the risk of AD is three times greater after the occurrence of stroke [72]. Stroke may result in neurodegeneration [73, 74], resulting in the rapid cognitive decline observed in AD patients [75]. It has even been proposed that stroke may be the underlying cause of 50% of AD cases [74]. Conversely, individuals presenting with severe cognitive impairments, and possibly AD, may be at a greater risk for the development of stroke

The amyloid hypothesis of AD was long held as the prevailing theory explaining the etiology of AD. However, emerging evidence compiled from the last 20 years has suggested that the pathology associated with AD is vascular in origin. The vascular hypothesis of AD states that pre-existing cardiovascular dysfunction such as stroke, hypertension and atherosclerosis results in chronic cerebral hypoperfusion that could encourage the onset of AD. Several lines of evidence have been provided in support of this hypothesis. For example, it has been shown that cerebrovascular dysfunction precedes cognitive decline and the onset of neurodegenera‐ tive changes in AD and AD animal models [12, 13]. In rhesus monkeys, dystrophic axons labeled with amyloidogenic enzyme, BACE1, were found in close proximity or in direct contact with cortical blood vessels [78], asserting a tight association with AD pathology and vascular dysfunction. Clinical and epidemiological evidence provides further support of the vascular

AD patients show a greater degree of vascular narrowing of carotid arteries [65] and cerebral arteries of the Circle of Willis [79, 80]. In addition, large artery CVD was positively correlated to the frequency of neuritic plaques [81]. Several vascular risk factors such stroke (silent infarcts, transient ischemic attacks), atherosclerosis, hypertension, heart disease (coronary artery disease, atrial fibrillation) and diabetes mellitus have been associated with an increased risk AD-type dementia [82]. Between 60 to 90% of AD patients exhibit various cerebrovascular pathologies including White matter lesions, cerebral amyloid angiopathy (CAA), microin‐ farcts, small infarcts, hemorrhages and microvascular degeneration [12-16]. It believed that cardiovascular dysfunctions act as a nidus for accelerated Aβ deposition resulting in the onset

Aberrant blood brain barrier (BBB) function exposes neurons to neurotoxic substances. Chronic cerebral hypoperfusion is believed to render the brain more vulnerable to various insults, resulting in AD and associated cognitive loss [84]. Clinical observations in AD patients

as AD.

414 Understanding Alzheimer's Disease

or CVD [76, 77].

hypothesis.

of AD [83].

A functional consequence associated with BBB dysfunction is the resultant impairment in cerebral hemodynamics. AD impairs autoregulation, the mechanism that is responsible for the stabilization of blood flow to the brain in response to changes in cerebral perfusion pressure [94]. In an APP x PS1 mouse model neurovascular coupling, the process in which activation of a brain region evokes a local increase in blood flow, was impaired [95]. Finally, AD has shown to adversely affect vasomotor/vascular reactivity, the process that mediates vasodila‐ tory or vasoconstrictor responses of cerebral blood vessels to hypercapnic or hypocapnic stimuli (ie. global or regional brain blood flow response to systemic changes in arterial CO2) [96-98]. Cumulatively, the impairment of these processes adversely affects cerebral blood regulation that, in turn, would negatively affect nutrient availability to neurons. This would result in cerebral hypoperfusion, a process that is widely believed to initiate the onset of AD pathology.

There are a number of known direct links between biochemical pathways central to AD and hypoxia/ischemia. A rat model for vascular cognitive impairment has been devel‐ oped referred to as the two-vessel occlusion model of cerebral ischemia. Studies found decreased cerebral blood flow up to 4 weeks, cognitive deficits, APP proteolysis to form Aβ-sized fragments [99-101]. Other studies have observed an overexpression of Aβ per‐ sisting for up to 3 months after surgery [102] and cognitive impairment [103], strongly suggesting that decreased CBF is a key mediator in the pathophysiology of AD. Several studies have been able to identify some of the molecular mechanisms as to how hypoxia/ ischemia exerts its effects on AD-related genes.

APP expression increases following chronic cerebral hypoperfusion and ischemia [104, 105], and a greater proportion of APP is proteolytically cleaved by increased activity of amyloido‐ genic enzyme, BACE1, which is concurrently increased in AD following ischemic events [106]. Hypoxia inducible factor-1α (HIF-1α) plays an essential role in cellular and systemic responses to low oxygen and has been found to increase BACE1 mRNA expression [107]. Furthermore, BACE1 stabilization is enhanced in AD in addition to a decrease in its trafficking [108, 109]. Increased BACE results in greater γ-secretase-mediated production of Aβ [110]. In an APP overexpressing mouse model, chronic cerebral hypoperfusion as the result of cerebral amyloid angiopathy (pathological deposition of Aβ1-40 in brain blood vessels) was followed by an increased rate of leptomeningeal Aβ precipitating the risk of microinfarcts [111]. Hypoxia/ ischemia not only causes increased amyloidogenic cleavage of APP and greater Aβ production, but also impairs Aβ degradation and trafficking [12, 112].

[132]. It has been suggested that differences in the clinical observations in AD and VaD patients may be due to the type, severity and location of vascular damage [133-135]. Furthermore, perturbations in vascular hemodynamics have been observed in VaD and AD [136, 137], however, AD patients had comparatively less impairment in cerebral perfusion than those with VaD [138] suggesting that hemodynamic disturbances may underlie different types of dementia [138]. While the precise mechanism that vascular risk factors initiate cognitive decline remains elusive [139], T2DM have been identified as an important contributing factor

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 417

**Associations between vascular dementia and Alzheimer's dementia** While regarded as two separate conditions, AD and VaD share common cerebrovascular pathologies such as CAA, endothelial cell and vascular smooth muscle cell degeneration, macro- and microinfarcts, hemorrhage and white matter changes [140-142]. These shared pathologies have been shown epidemiologically with almost 35% of AD patients showing evidence of cerebral infarction at autopsy [143, 144], and, conversely, VaD patients display AD-like pathology in the absence of pre-existing AD [145]. It has been postulated that CVD, thought to be the etiology of both disorders, not only result in dementia but also increase the likelihood of individuals with AD-

**Insulin/IGF-1 pathway activation.** The brain is a major metabolic organ that accounts for ~25% of the body's total glucose use [28, 29]. While glucose uptake in peripheral tissues requires insulin, in the brain this is considered to be an insulin-independent process. Insulin, however, along with Insulin-like Growth Factor-1 (IGF-1), are required for proper brain function as they provide critical neurotrophic support for neurons. IGF-1 and insulin share similar amino acid sequences/ tertiary structures [148] and are known to bind to and activate one anothers' receptors [149]. Both insulin and IGF-1 receptors are tyrosine kinases [150-152] that, when activated, phosphorylate substrate proteins such as IRS. IRS phosphorylation leads to down‐ stream activation of PI3K and Akt, a serine/threonine kinase and key mediator of insulin/ IFG-1's neurotrophic effects. Neuronal processes known to be, at least in part, under the control of insulin/IGF-1 include regulation of apoptotic proteins, transcription of both survival and

The source of brain insulin remains controversial. While preproinsulin mRNA has been reported in the neurons [153-155], very little insulin is synthesized in the brain [156]. Addi‐ tionally, glial cells have been found not to be involved in insulin production [157], therefore, it is recognized that the majority of insulin in the brain is produced by pancreatic β cells [158-161]. In contrast, IGF-1 is produced locally in the brain and does not depend on growth

Neuronal insulin receptors are different than those found in the periphery [162]. Insulin receptors are present in one of two isoforms; the IR-A isoform that lacks exon 11 that the other isoform, IR-B, expresses [163, 164]. A major functional difference between the two isoforms is

pro-death genes, neurite outgrowth, and activity of metabolic proteins.

hormone influence as is the case of liver and other tissues [148].

to the development of VaD.

related lesions for developing dementia [146, 147].

**3. Insulin signaling in the brain**

Decreased Aβ-degrading enzymes in response to hypoxic conditions increase the likelihood of developing pathological levels of Aβ in the brain [113-115]. Aβ serves not only as the end result of a pathological cascade, but Aβ itself has been found to contribute to dysfunction in components of the neurovascular unit. In endothelial cells Aβ was observed to decrease endothelial cell proliferation and accelerate senescence of endothelial cells in vivo and in vitro, inhibit VEGF-induced activation of Akt and eNOS in endothelial cells [116, 117]. Aβ has been found to decrease eNOS (via PKC-dependent pathway) resulting in decreased vascular tonus and decreased substance P-induced vasodilation of the basilar artery[118, 119]. In vascular smooth muscle cells (VSMCs), Aβ affects cellular morphological changes [120] and increases expression of transcription factors, serum response factor and myocardin, resulting in decreased Aβ clearance by downregulating LRP expression [12]. Finally, Aβ has been shown to cause retraction and swelling of astrocyte endfeet in an AD mouse model with CAA [121] as well as increase cholinergic denervation of cortical microvessels which, taken together, results in impaired functional hyperemia [122].

**Type 2 diabetes and vascular dementia** A significant number of population-based studies have indicated an increased risk for the development of dementia attributed to T2DM [23-25]. Due to the importance of insulin in the regulation of several cardiovascular functions, it is unsurprising that insulin resistance plays a role in the cerebrovascular mechanisms of T2DMinduced dementia. The presence of brain infarcts in demented diabetics who did not have AD has been reported 123. Interestingly, the association between T2DM and the development of AD and VaD has been found to be independent of hypertension and hypercholesterolemia [23] indicating that is CVD alone is not sufficient to initiate dementia. Non-cerebrovascular mechanisms such as peripheral hyperinsulinemia and generation of advanced glycation endproducts also play in the etiology of T2DM-related dementia [124]. Studies have shown that the increased risk of developing vascular dementia was greater than developing AD in type 2 diabetics [7, 125, 126], indicating that although symptomatically similar and frequently confused [127], their etiologies are distinct.

**Vascular dementia versus Alzheimer's dementia** The leading cause of dementia is Alzheim‐ er's disease accounting for 70-90% of all cases [127], while vascular dementia (VaD) accounts for the majority of the remaining incidents of dementia [128]. They share common risk factors including hypertension, diabetes mellitus, and hyperlipidemia. [129], highlighting the tight association between these two forms of dementia. In fact, it is now widely believed that AD and VaD are frequently present in the same brain. So-called "mixed dementia" has been observed in elderly people with cardiovascular risk factors in addition to slow progressive cognitive decline [130].

Differing clinical manifestations separate VaD from AD dementia. For example, VaD progres‐ sion appears more varied than AD in relation to symptoms, its rate of progression and the disease outcome [131]. Increased damage to the ganglia-thalamo-cortical circuits specific to VaD results in problems with attention and the planning and speed of mental processing whereas the primary impairments characteristic of AD are memory and language-related [132]. It has been suggested that differences in the clinical observations in AD and VaD patients may be due to the type, severity and location of vascular damage [133-135]. Furthermore, perturbations in vascular hemodynamics have been observed in VaD and AD [136, 137], however, AD patients had comparatively less impairment in cerebral perfusion than those with VaD [138] suggesting that hemodynamic disturbances may underlie different types of dementia [138]. While the precise mechanism that vascular risk factors initiate cognitive decline remains elusive [139], T2DM have been identified as an important contributing factor to the development of VaD.

**Associations between vascular dementia and Alzheimer's dementia** While regarded as two separate conditions, AD and VaD share common cerebrovascular pathologies such as CAA, endothelial cell and vascular smooth muscle cell degeneration, macro- and microinfarcts, hemorrhage and white matter changes [140-142]. These shared pathologies have been shown epidemiologically with almost 35% of AD patients showing evidence of cerebral infarction at autopsy [143, 144], and, conversely, VaD patients display AD-like pathology in the absence of pre-existing AD [145]. It has been postulated that CVD, thought to be the etiology of both disorders, not only result in dementia but also increase the likelihood of individuals with ADrelated lesions for developing dementia [146, 147].
