Chronic α-Synuclein Accumulation in Rat Hippocampus Induces Lewy Bodies Formation and Specific Cognitive Impairments

Abstract

Occurrence of Lewy bodies (LBs)/Lewy neurites (LNs) containing misfolded fibrillar a-synuclein (a-syn) is one of the pathologic hallmarks of memory impairment-linked synucleinopathies, such as Parkinson's disease (PD) and dementia with LBs (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropathological substrates for cognitive symptoms are still elusive. Here, recombinant mouse a-syn fibrils were bilaterally injected in the hippocampus of female Sprague Dawley rats, which underwent behavioral testing for sensorimotor and spatial learning and memory abilities. No sensorimotor deficits affecting Morris water maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months postinjection. These deficits were associated to a time-dependent increase in the levels of phosphorylated a-syn at Ser129 and in the stereologically estimated numbers of proteinase K (PK)-resistant a-syn aggregates within the hippocampus. Interestingly, pathologic a-syn aggregates were found in the entorhinal cortex and, by 12 months postinjection, also in the vertical limb of the diagonal band and the piriform cortices. No pathologic a-syn deposits were found within the substantia nigra (SN), the ventral tegmental area (VTA), or the striatum, nor was any loss of dopaminergic, noradrenergic, or cholinergic neurons detected in a-syn-injected animals, compared with controls. This would suggest that the behavioral impairments seen in the a-syn-injected animals might be determined by the long-term a-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits.

Characterisation of functional deficits induced by AAV overexpression of alpha-synuclein in rats

“…These data exclude a deficit which is due to a primary deficit in sensory perception nor execution of a motoric response per se , but rather a deficit in relative egocentric space. Cognitive deficits have only been modelled in AAV-h-aSYN or pre-formed fibrils (PFFs) injection models with limited success, e.g., spatial working and reference memory on the Morris water maze test when aSYN was overexpressed in the VTA and septum ( Hall et al, 2013 ) or following injection of PFFs into the hippocampus ( Kasongo et al, 2020 ). AAV-h-aSYN overexpression in both neonate mice and rats has generally led to the development of pathology, but not to robust deficits in non-motor domains ( Aldrin-Kirk et al, 2014 ; Delenclos et al, 2017 ).…”

Nuclear localization of alpha-synuclein affects the cognitive and motor behavior of mice by inducing DNA damage and abnormal cell cycle of hippocampal neurons

“…There is increasing evidence that the pathological accumulation of α-syn in the hippocampus may lead to cognitive impairment ( Regensburger et al, 2014 ; Kasongo et al, 2020 ; Zhang et al, 2022 ). Our research showed that compared with other groups, nuclear localization of α-syn caused DNA damage response in hippocampal neuron earlier, induced apoptosis and inflammatory reaction, thereby causing more rapid and serious cognitive impairment and motor impairment in mice.…”

Cognitive profiling and proteomic analysis of the modafinil analogue S-CE-123 in experienced aged rats

“…α-Synuclein, also down-regulated in the CE-123 group, is a presynaptic protein that under physiological conditions associates with synaptic vesicle membranes and regulates synaptic vesicle trafficking 50 . However, increased levels of α-synuclein lead to formation of aggregates and produce a physiological defect in synaptic vesicle recycling, which is associated with compromised neurotransmission 51 , 52 and linked to Parkinson’s disease and other neurodegenerative diseases 50 , 53 . The GO terms cluster “receptor-mediated endocytosis” comprising of GO terms like synaptic vesicle recycling, synaptic vesicle transport, receptor internalization, etc., was one of the most prominent processes modulated by CE-123 treatment (Fig.…”