There has been increased interest in studying the pathology of veins and venules, not only in the context of CAA, but also in dementia 3, 4, 14, 15, 16. The venous system of the cerebrovasculature, until recently, has been under-studied in CAA and, in association, Alzheimer’s Disease (AD) 13. Due to their highly integrative nature, there has been a need to investigate the role of the cerebrovasculature and of CAA to understand how the vasculature contributes to AD. Despite it being a distinct pathology 12, CAA is highly comorbid with AD, with prevalence of 80–90% in AD patients 9, 10. CAA is a small vessel disease defined as the accumulation of various amyloid proteins, leading to cerebrovascular dysfunction and severe clinical symptoms including stroke, intracerebral hemorrhages, and dementia 6, 8, 11. Aβ aggregates also build up in the walls of the vasculature, a pathology known as cerebral amyloid angiopathy (CAA) 8, 9, 10. The build-up of Aβ results in the formation of amyloid plaques spreading through the cortex then into the hippocampus 4, 5, leading to neuronal death and brain atrophy 6, 7. The underlying mechanisms of this disease is distinctly marked by the accumulation of two proteins extracellular amyloid-beta peptides (Aβ) and intracellular hyperphosphorylated tau 2, 3. AD is characterized by several clinical symptoms including cognitive decline, memory impairment, and loss of activities of daily living 1, 2, 3. With Alzheimer’s disease (AD) being the most common form of dementia in the elderly 1, there has been an overwhelming drive in research to understand the intricacies of this complex neurodegenerative disease for the discovery of therapeutics and treatment. Overall, understanding venular and arteriolar amyloid pathology provides insight into the complex connection between CAA and AD. Lastly, significant arteriolar amyloid accumulates relative to venular amyloid deposition in AD progression. Histopathological analysis indicates a significant age effect for both arteriolar and venular amyloid accumulation, with accumulation initiated in the somatosensory cortex followed by the motor and cingulate cortex. Mass spectrometric analyses of isolated cortical parenchymal plaques, arteriolar and venular amyloid demonstrated presence of Aβ in all three samples, as well as proteins known to be associated with AD. Antibodies targeting the amyloid-beta peptide (Aβ) sequence suggest morphological differences between arteriolar and venular amyloid. Therefore, this study sought to examine venular amyloid pathology and its relationship to arteriolar amyloidosis throughout AD progression in the TgF344-AD rat model. CAA research has primarily focused on arterioles and capillaries, overlooking the draining venules. For this reason, interest in understanding the underlying vascular pathologies that contribute to AD remain. Strong evidence demonstrates a significant association between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD).
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