Journal Article

DZNE-2025-01121

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Autophagy activation ameliorates cognitive deficits and alpha-synuclein pathology in an adeno-associated viral vector mediated rat model of Lewy body disorders.

Cinar, E. ; Yalcin-Cakmakli, G. ; Akyel, H. ; Ulusoy, A.DZNE* ; Tel, B. C. ; Elibol, B.

2025
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.pbb.2025.174096

Abstract: Lewy body disorders (LBD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by the aggregation of alpha-synuclein (a-syn). Despite shared pathological features, these disorders have distinct clinical characteristics, in terms of both motor and cognitive symptoms. We created a unique rat model of dual-site injection of adeno-associated viral vectors carrying human a-syn (AAV5-h-a-syn) simultaneously and bilaterally into the substantia nigra and dentate gyrus, to recapitulate both nigrostriatal and hippocampal-based a-syn pathology associated with PDD and DLB. Inspired by the distinct pathological features of the model, namely the CA2-dominated accumulation of phosphorylated a-syn, in the current study we aimed to evaluate comparatively the consequences of autophagic induction on a-syn pathology in these targeted areas. This was achieved by the chronic administration of rapamycin, for 8 weeks starting 10 weeks post-AAV injections. Behavioral assessments were conducted by evaluation of locomotor activity, anxiety-related behavior, object and spatial learning and memory. Histopathological examinations involved in-depth analysis of a-syn pathology, neuronal and synaptic integrity and autophagic markers. Results demonstrated that rapamycin significantly ameliorated cognitive deficits and reduced phosphorylated a-syn accumulation, significantly in CA2 throughout all its sublayers and partially in CA3 sublayers. Despite no alteration in NeuN and TH levels, synaptophysin expressions were decreased in both the hippocampus and striatum in a-syn overexpressing animals, which were partially restored by rapamycin treatment. Intriguingly, autophagic activation, as indicated by the increased expression of beclin-1, LC3-I/II, p62, and Atg proteins, was predominantly observed in the hippocampus but not in the striatum, suggesting region-specific differential response to autophagic induction in terms of a-syn pathology. This dual-site injection model provides a valuable tool for studying a-syn-related dementia and evaluating potential restorative therapies. Our findings underscore the importance of autophagy-targeting early interventions to alleviate cognitive deficits by reducing hippocampal a-syn burden in LBD.

Keyword(s): Animals (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; alpha-Synuclein: genetics (MeSH) ; Autophagy: drug effects (MeSH) ; Autophagy: physiology (MeSH) ; Rats (MeSH) ; Dependovirus: genetics (MeSH) ; Lewy Body Disease: pathology (MeSH) ; Lewy Body Disease: metabolism (MeSH) ; Lewy Body Disease: psychology (MeSH) ; Lewy Body Disease: therapy (MeSH) ; Male (MeSH) ; Disease Models, Animal (MeSH) ; Genetic Vectors (MeSH) ; Cognitive Dysfunction: therapy (MeSH) ; Sirolimus: pharmacology (MeSH) ; Humans (MeSH) ; Rats, Sprague-Dawley (MeSH) ; Alpha-synucleinopathies ; CA2 ; Dementia ; Hippocampus ; Parkinson's disease ; Rapamycin ; Stratum pyramidale ; Synaptic integrity

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Contributing Institute(s):

1. Parkinson's and Spatial Omics (AG Ulusoy)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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