Dataset Information

Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α-syn co-pathology.

ABSTRACT: Several degenerative brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid-β (Aβ) and α-synuclein (α-syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α-syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP-transgenic mice expressing APP695^KM670/671NL and PSEN1^L166P under the control of the neuron-specific Thy-1 promoter (referred to here as APPPS1) and APPPS1 mice co-expressing SNCA^A30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age-dependent increase in Aβ load in the olfactory bulb of APP-transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α-syn significantly diminished the endogenous and seed-induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.

SUBMITTER: Friesen M

PROVIDER: S-EPMC9048518 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α-syn co-pathology.

Friesen Marina M Ziegler-Waldkirch Stephanie S Egenolf Milena M d'Errico Paolo P Helm Christina C Mezö Charlotte C Dokalis Nikolaos N Erny Daniel D Katzmarski Natalie N Coelho Romina R Loreth Desirée D Prinz Marco M Meyer-Luehmann Melanie M

Brain pathology (Zurich, Switzerland) 20211029 3

Several degenerative brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid-β (Aβ) and α-synuclein (α-syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α-syn in Aβ aggregation and the arising characteristic olfactory impairmen ...[more]

PMID: 34713522

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Project description:Progressive aggregation of the protein alpha-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson's disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of α-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in studies of familial and sporadic forms of PD. However, how these genes affect α-syn aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of α-syn aggregation, using an α-syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated α-syn aggregation in mouse primary neurons. Conversely, α-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S transgenic mice, we observed acceleration of α-syn aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and behavioral deficits. To validate our findings in a human context, we established a novel human α-syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human α-syn PFFs triggered aggregation of endogenous α-syn in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced α-syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and α-syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, beyond cases caused by LRRK2 mutations.

Dataset Information

Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α-syn co-pathology.

Publications

Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α-syn co-pathology.

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