Review argues that cardiovascular disease–related hypoperfusion and oxidative stress drive cytoskeletal and microtubule disintegration across neurodegenerative disorders and highlights alpha-synuclein-mediated impairment of microtubule polymerization in substantia nigra dopaminergic neurons…

Identifies a heart–brain axis and actionable mechanisms (microtubule destabilization, oxidative stress, vascular dysfunction, and proteinopathies) that point to potential therapeutic strategies and biomarkers such as microtubule stabilizers, antioxidant/vascular interventions, and cytoskeletal…

Neurodegenerative diseases, such as Alzheimer's disease, vascular dementia, Parkinson's disease, frontotemporal dementia, and cognitive decline associated with stroke, have a similar clinical trait involving the alteration of microtubule dynamics and cytoskeletal integrity. The neuronal cytoskeleton is essential for facilitating axonal transport, synaptic connections, and providing structural support. In Alzheimer's disease and vascular dementia, tau protein undergoes hyperphosphorylation and dissociates from microtubules, forming insoluble aggregates that obstruct intracellular transport and destabilize microtubule structure. Additionally, region-specific posttranslational changes of tubulin are modified, further impairing cytoskeletal control. In Parkinson's disease, the aggregation of α-synuclein induces oxidative damage and directly impairs microtubule polymerization, especially in the dopaminergic neurons of the substantia nigra. Stroke induces acute ischemia and reperfusion injury, resulting in surges of reactive oxygen and nitrogen species, disruption of the blood-brain barrier, and neuroinflammatory cascades that rapidly destroy cytoskeletal proteins and alter microglial phenotypes. Cardiovascular conditions, including hypertension, heart failure, and atherosclerosis, lead to persistent cerebral hypoperfusion, which promotes progressive neuronal damage and alters tubulin expression and organization. Cardiovascular complications intensify oxidative stress and impair neurovascular coupling, establishing a detrimental cycle that accelerates cytoskeletal disintegration and neural impairment. Collectively, such conditions demonstrate a heart-brain axis in which cardiovascular problems directly lead to microtubule disintegration and dementia. Understanding these pathways provides a unified framework for cytoskeletal biomarkers and novel therapeutic approaches to preserve neuronal structure in various neurological conditions.