Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts

Matthew A Weber; Gemma Kerr; Ramasamy Thangavel; Mackenzie M Conlon; Hisham A Abdelmotilib; Oday Halhouli; Qiang Zhang; Joel C Geerling; Nandakumar S Narayanan; Georgina M Aldridge

doi:10.1101/2023.01.31.526365

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Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts

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Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts

Matthew A Weber, Gemma Kerr, Ramasamy Thangavel, Mackenzie M Conlon, Hisham A Abdelmotilib, Oday Halhouli, Qiang Zhang, Joel C Geerling, Nandakumar S Narayanan and Georgina M Aldridge

bioRxiv

Cold Spring Harbor Laboratory Press

02/03/2023

DOI: 10.1101/2023.01.31.526365

PMCID: PMC9915664

PMID: 36778400

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https://doi.org/10.1101/2023.01.31.526365View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Parkinson's disease dementia (PDD) and Lewy Body dementia (LBD) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. These patients have a neuropsychological pattern of deficits that include executive dysfunction, including abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in LBD and PDD. To investigate the consequences of α-syn pathology in the cortex, we injected human α-syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced α-syn deposition in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or working memory but did mildly alter behavioral flexibility as measured by reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology adds to our understanding of the etiology of varied symptoms in PDD and LBD. Competing Interest Statement The authors have declared no competing interest.

Dementia

Etiology

Inflammation

Neurodegenerative Diseases

Pathology

Brain stem

Dementia disorders

Executive function

Fibrils

Lewy bodies

Mesencephalon

Movement disorders

Parkinson's disease

Prefrontal cortex

Reversal learning

Short term memory

Synuclein

Details

Title: Subtitle: Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts
Creators: Matthew A Weber - University of Iowa
Gemma Kerr - University of Iowa
Ramasamy Thangavel - University of Iowa
Mackenzie M Conlon - University of Iowa
Hisham A Abdelmotilib - University of Iowa
Oday Halhouli - University of Iowa
Qiang Zhang - University of Iowa
Joel C Geerling - University of Iowa
Nandakumar S Narayanan - University of Iowa
Georgina M Aldridge - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.01.31.526365
PMID: 36778400
PMCID: PMC9915664
Publisher: Cold Spring Harbor Laboratory Press; Cold Spring Harbor
Language: English
Date posted: 02/03/2023
Academic Unit: Neurology; Iowa Neuroscience Institute
Record Identifier: 9984366049002771

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