Imaging of Leukocyte Trafficking in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by a progressive decline of cognitive functions. The neuropathological features of AD include amyloid beta (Aβ) deposition, intracellular neurofibrillary tangles derived from the cytoskeletal hyperphosphorylated tau protein, amyloid angiopathy, the loss of synapses, and neuronal degeneration. In the last decade, inflammation has emerged as a key feature of AD, but most studies have focused on the role of microglia-driven neuroinflammation mechanisms. A dysfunctional blood–brain barrier has also been implicated in the pathogenesis of AD, and several studies have demonstrated that the vascular deposition of Aβ induces the expression of adhesion molecules and alters the expression of tight junction proteins, potentially facilitating the transmigration of circulating leukocytes. Two-photon laser scanning microscopy (TPLSM) has become an indispensable tool to dissect the molecular mechanisms controlling leukocyte trafficking in the central nervous system (CNS). Recent TPLSM studies have shown that vascular deposition of Aβ in the CNS promotes intraluminal neutrophil adhesion and crawling on the brain endothelium and also that neutrophils extravasate in the parenchyma preferentially in areas with Aβ deposits. These studies have also highlighted a role for LFA-1 integrin in neutrophil accumulation in the CNS of AD-like disease models, revealing that LFA-1 inhibition reduces the corresponding cognitive deficit and AD neuropathology. In this article, we consider how current imaging techniques can help to unravel new inflammation mechanisms in the pathogenesis of AD and identify novel therapeutic strategies to treat the disease by interfering with leukocyte trafficking mechanisms.

Neutrophils in animal models of autoimmune disease

“…These exciting and unexpected results suggest that neutrophils may play additional, unanticipated roles in neurodegenerative disease (perhaps regulating vascular permeability as in EAE models). Clearly, this is an area of exciting research [132]. …”

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

“…Neutrophil activation and related oxidative stress have been associated with AD pathology in humans [5][6][7]. Evidence from clinical and animal studies suggests that neutrophils may translocate to and co-localize with the cerebral blood vessels and amyloid plaques within the brain parenchyma [8][9][10][11]. Recent animal studies have also shown that neutrophil adhesion in the cerebral small vessels may mediate changes in cognition [12,13].…”

Análise da patogênese da doença de Alzheimer: revisão narrativa da literatura

“…Doenças neurodegenerativas, como a doença de Alzheimer (DA), têm sido cada vez mais objeto de estudo em inúmeras pesquisas científicas. [1][2][3][4][5][6][7][8][9][10][11][12] Estimativas da OMS sinalizam mais de 47 milhões de indivíduos acometidos por algum tipo de demência mundialmente, com incidência anual de diagnósticos superando 7,5 milhões de casos. Desses, a DA é responsável por aproximadamente 70% dos diagnósticos.…”

“…14 imunológicas são alguns desses fatores pontuados. [2][3][4][5][6][7][8][9] Nesse sentido, ainda que exista a correlação genética com alguns casos clínicos de DA, outros fatores de risco além do próprio envelhecimento também devem ser lembrados, tais como o traumatismo cranioencefálico, hipertensão, diabetes e demais síndromes metabólicas. 14 Em estudos anatomopatológicos, a DA é caracterizada por placas neurais formadas por depósito β-amiloide e emaranhados fibrilares abundantes em proteína Tau hiperfosforilada.…”