Three-Dimensional Imaging of Fibrinogen and Neurovascular Alterations in Alzheimer's Disease

Mario Merlini; Elif G Sozmen; Keshav S Subramanian; Alissa L Nana; William W Seeley; Katerina Akassoglou

doi:10.1007/978-1-0716-2655-9_5

Three-Dimensional Imaging of Fibrinogen and Neurovascular Alterations in Alzheimer's Disease

Methods Mol Biol. 2023:2561:87-101. doi: 10.1007/978-1-0716-2655-9_5.

Authors

Mario Merlini^{1

2}, Elif G Sozmen^{1

2

3}, Keshav S Subramanian², Alissa L Nana³, William W Seeley³, Katerina Akassoglou^{4

5

6}

Affiliations

¹ Gladstone UCSF Center for Neurovascular Brain Immunology, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
³ Department of Neurology, Weill Institute of Neurosciences, University of California, San Francisco, CA, USA.
⁴ Gladstone UCSF Center for Neurovascular Brain Immunology, San Francisco, CA, USA. [email protected].
⁵ Gladstone Institute of Neurological Disease, San Francisco, CA, USA. [email protected].
⁶ Department of Neurology, Weill Institute of Neurosciences, University of California, San Francisco, CA, USA. [email protected].

Abstract

Cerebrovascular dysfunction is a hallmark of Alzheimer's disease (AD) that is linked to cognitive decline. However, blood-brain barrier (BBB) disruption in AD is focal and requires sensitive methods to detect extravasated blood proteins and vasculature in large brain volumes. Fibrinogen, a blood coagulation factor, is deposited in AD brains at sites of BBB disruption and cerebrovascular damage. This chapter presents the methodology of fibrinogen immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs (iDISCO) which, when combined with immunolabeling of amyloid β (Aβ) and vasculature, enables sensitive detection of focal BBB vascular abnormalities, and reveals the spatial distribution of Aβ plaques and fibrin deposits, in large tissue volumes from cleared human brains. Overall, fibrinogen iDISCO enables the investigation of neurovascular and neuroimmune mechanisms driving neurodegeneration in disease.

Keywords: 3D imaging; Alzheimer’s disease (AD); Biomarker; Blood-brain Barrier; Fibrinogen; Microscopy; Neurodegeneration; Neuroinflammation; Neurovascular; Tissue Clearing; iDISCO.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Fibrinogen / metabolism
Humans
Imaging, Three-Dimensional
Plaque, Amyloid

Substances

Amyloid beta-Peptides
Fibrinogen

Abstract

Publication types

MeSH terms

Substances

Grants and funding