The neurovascular unit (NVU) comprises brain endothelial cells, pericytes, vascular smooth muscle cells, glia, and neurons. It controls the blood-brain barrier (BBB) and cerebral blood flow, maintaining the chemical environment necessary for neuronal function. BBB dysfunction is linked to neurodegenerative disorders like Alzheimer's disease (AD), where vascular insults contribute to neuronal degeneration. Neurons depend on blood vessels for oxygen, nutrients, and removal of toxic metabolites. The brain consumes a large proportion of the body's oxygen and glucose, highlighting the importance of the circulatory system. Neurodegenerative disorders such as AD and amyotrophic lateral sclerosis (ALS) are associated with microvascular dysfunction, BBB breakdown, and vascular factors. These issues impair cerebral blood flow and the clearance of neurotoxic molecules, leading to neuronal dysfunction and neurodegeneration. The NVU includes vascular cells, glia, and neurons, working together to maintain BBB integrity and cerebral blood flow. BBB breakdown can lead to the accumulation of harmful molecules, hypoperfusion, and hypoxia, which damage neurons. In AD, vascular dysfunction precedes neuronal changes, contributing to amyloid-β accumulation and neurodegeneration. The BBB is crucial for clearing amyloid-β, and its dysfunction leads to increased amyloid-β levels and neurotoxic effects. The two-hit vascular hypothesis suggests that primary vascular damage (hit one) initiates non-amyloidogenic pathways, while secondary amyloid-β accumulation (hit two) exacerbates neurodegeneration. Vascular factors such as VEGF, TGF-β, and growth factors play roles in BBB integrity and neurovascular repair. Therapeutic strategies targeting the vasculoneuronal-inflammatory triad, including VEGF and angiogenin, show promise in treating AD and ALS. These approaches aim to improve vascular function, BBB integrity, and reduce neuroinflammation. The development of delivery strategies for vascular factors is essential for their systemic use in neurodegenerative diseases. Overall, vascular dysfunction is a key contributor to neurodegeneration, and targeting neurovascular pathways offers potential therapeutic opportunities for diseases like AD and ALS.The neurovascular unit (NVU) comprises brain endothelial cells, pericytes, vascular smooth muscle cells, glia, and neurons. It controls the blood-brain barrier (BBB) and cerebral blood flow, maintaining the chemical environment necessary for neuronal function. BBB dysfunction is linked to neurodegenerative disorders like Alzheimer's disease (AD), where vascular insults contribute to neuronal degeneration. Neurons depend on blood vessels for oxygen, nutrients, and removal of toxic metabolites. The brain consumes a large proportion of the body's oxygen and glucose, highlighting the importance of the circulatory system. Neurodegenerative disorders such as AD and amyotrophic lateral sclerosis (ALS) are associated with microvascular dysfunction, BBB breakdown, and vascular factors. These issues impair cerebral blood flow and the clearance of neurotoxic molecules, leading to neuronal dysfunction and neurodegeneration. The NVU includes vascular cells, glia, and neurons, working together to maintain BBB integrity and cerebral blood flow. BBB breakdown can lead to the accumulation of harmful molecules, hypoperfusion, and hypoxia, which damage neurons. In AD, vascular dysfunction precedes neuronal changes, contributing to amyloid-β accumulation and neurodegeneration. The BBB is crucial for clearing amyloid-β, and its dysfunction leads to increased amyloid-β levels and neurotoxic effects. The two-hit vascular hypothesis suggests that primary vascular damage (hit one) initiates non-amyloidogenic pathways, while secondary amyloid-β accumulation (hit two) exacerbates neurodegeneration. Vascular factors such as VEGF, TGF-β, and growth factors play roles in BBB integrity and neurovascular repair. Therapeutic strategies targeting the vasculoneuronal-inflammatory triad, including VEGF and angiogenin, show promise in treating AD and ALS. These approaches aim to improve vascular function, BBB integrity, and reduce neuroinflammation. The development of delivery strategies for vascular factors is essential for their systemic use in neurodegenerative diseases. Overall, vascular dysfunction is a key contributor to neurodegeneration, and targeting neurovascular pathways offers potential therapeutic opportunities for diseases like AD and ALS.