*4.2.1 Alzheimer's disease*

*Connectivity and Functional Specialization in the Brain*

molecules and causing BBB permeability [81].

*4.1.2 Intracerebral hemorraghe*

parenchyma [82].

**Figure 3.**

induced brain injury by stroke, various mechanisms in the neurovascular bed can trigger oxidative stress, including mitochondrial dysfunction, increase vasogenic mediators, glutamate release, and depletion of antioxidant defense system. Mitochondria are both important intracellular organelles for energy metabolism organelles, the main intracellular source of ROS, and important targets for I/R brain injury [79]. During stroke, inflammatory cytokines, oxidative stress, and Ca+2 overload stimulate the mitochondria, inducing the production of higher ROS levels, thereby triggering the mitochondrial necrosis pathway and leading to cell death [80]. In addition, endothelial cells, and immune cells produce large amounts of ROS during the cerebral ischemia phase, which in turn induce the activation of nuclear factor-κappa B (NF-κB), inducible endothelial nitric oxide (iNOS), and proinflammatory factors, triggering the upregulation of vascular endothelial cell adhesion

*and apoptotic mechanisms depending on the severity of insult. Created with BioRender.com.*

*A schematic view of ischemic stroke and intracerebral hemorrhage mechanisms. Activation of glutamate receptors following ischemic stroke leads to excitotoxicity and calcium influx, this impairs the neuronal homeostasis leading to activation of several calcium dependent pathways that include proteases and nucleases. Reperfusion aggravates the cerebral parenchyma damage by forming free radicals that damage the membranes and proteins. Further, the opening of mitochondrial permeability transition pore releases various proapoptotic molecules that activate apoptotic cell death in cerebral parenchyma. In intracerebral hemorrhage the initial bleed causes physical disruption of the cellular architecture of the brain and the mass of the haematoma may increase intracranial pressure which can compress brain regions, increasing neuronal death result of necrotic* 

Between 10 and 15% of all strokes in the USA are intracerebral hemorrhages, which has higher morbidity and mortality when compared to ischemic strokes. Multiple etiologies are associated with ICH, hypertension being the more common, followed by amyloid pathology, especially in older populations, vascular malformations, and coagulopathies [72]. After the initial bleed, there can be a continuous bleed for the next 24 hours, the so-called hematoma expansion. A delayed vascular disruption occurs after the first 24 hours; this includes BBB dysfunction, which can associate with edema formation and an influx of leukocytes into the brain

The role of ischemia in ICH-induced brain injury is controversial, as a reduction in blood flow may be a result rather than the cause of brain damage. This suggests that BBB's increased permeability is due to the direct effect of certain blood components (thrombin, fibrin, and hemoglobin, iron) or to the inflammatory response to these components [72]. This phenomenon may include further peripheral cell

**34**

Alzheimer's disease (AD) pathological hallmark is the accumulation of amyloid beta plaque deposits, which suggests the imbalance between its production and clearance rates may be due to a leaky BBB. The BBB dysfunction itself can also promote and accelerate the process of further AB production [84]. Diminished expression and dysfunction of ABC transporters at the BBB have been found in AD mice models [85], and two crucial BBB transporters in Abeta BBB's flow dynamics, p-glycoprotein LRP1, and RAGE have been identified as functionally impaired in AD. Expression of LRP1, which is in charge of the efflux of brain-derived Ab into blood across the BBB, is remarkably low at the BBB in AD patients' and AD models' brains [86]. Verapamil-PET studies in patients with mild AD, an exam that clinically assesses p-glycoprotein function, have found reduced activity of this transport in frontal, posterior cingulate, and the parietooccipital cortices, as well as in the hippocampus [87]. RAGE is a vital transporter that regulates the influx of circulating soluble ab intro the brain, which may promote neuroinflammation. Patients with AD develop increased levels of this transporter receptor both in brain endothelium and mural cells of the BBB [88].

There is enough evidence that associates AD with vascular disease at a pathological level [89]. Cerebral vessel pathology is not only a significant risk factor for AD but can also cause BBB disruption, as is the case with cerebral amyloid angiopathy [90]. Furthermore, changes in vascular biomarkers have been observed in preclinical AD before the development of cognitive impairment, and even before increases in routine AD biomarkers [91]. These findings support the two-hit vascular hypothesis of AD suggests that BBB dysfunction and brain hypoperfusion secondary to blood vessel damage may be the first hit that leads to ab accumulation and neuronal injury [92]. There is also evidence that at least two out of three BBB's main three cell lines are significantly compromised in AD. Accelerated pericyte degeneration and BBB breakdown is a distinguishing characteristic of AD-ApoE4 carriers mouse models [93]. On the other hand, astrocytic dysfunction, which has also been seen in AD models [84], may explain the hyperactivity of RAGE and hypoactivity of LRP1 in these patients' BBB. The pericyte degeneration initiates multiple pathways of neurodegeneration owing to the entry of several neurotoxic blood-derived proteins, including plasminogen, thrombin and fibrinogen which enter different areas of the CNS [93]. Plasmin, which is generated from circulating plasminogen, degrades the neuronal matrix protein laminin, thereby promoting neuronal injury. High concentrations of thrombin mediate neurotoxicity and memory impairment and accelerate BBB disruption [94].
