The Human Hippocampus in Parkinson’s Disease: An Integrative Stereological and Proteomic Study

Abstract

Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disease that is pathologically described as a six-stage α-synucleinopathy. In stage 4, α-synuclein reaches the hippocampus, inducing cognitive deficits, from which it progresses to the isocortex, leading to dementia. Among hippocampal fields, cornu ammonis 2 is particularly affected by this α-synucleinopathy and critical for cognitive decline. Volumetric studies using magnetic resonance imaging have produced controversial results, with only some reporting volume loss, whereas stereological data obtained using nonspecific markers do not reveal volume changes, neural or glial loss. Proteomic analysis has not been carried out in the hippocampus of patients with PD. Objective: This study aims to explain hippocampal changes in patients with PD at the cellular and proteomic levels. Methods: α-Synuclein inclusions, volume and neural (NeuN), microglial (Iba-1) and astroglial (GFAP) populations were stereologically analyzed. SWATH-MS quantitative proteomic analysis was also conducted. Results: Area fraction fractionator probe revealed a higher area fraction α-synucleinopathy in cornu ammonis 2. No volume change, neurodegeneration, microgliosis or astrogliosis was detected. Proteomic analysis identified 1,634 proteins, of which 83 were particularly useful for defining differences among PD and non-PD groups. Among them, upregulated (PHYIP, CTND2, AHSA1 and SNTA1) and downregulated (TM163, REEP2 and CSKI1) proteins were related to synaptic structures in the diseased hippocampus. Conclusion: The distribution of α-synuclein in the hippocampus is not associated with volumetric, neural or glial changes. Proteomic analysis, however, reveals a series of changes in proteins associated with synaptic structures, suggesting that hippocampal changes occur at the synapse level during PD.

Neurodegeneration and Astrogliosis in the Human CA1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer’s Disease

“…420300-9900), and quantification was performed with a 63× objective (Zeiss Plan-Apochromat 63×/1.4 oil DIC, Ref. 420782–9900) ( Figure 1 ) [ 72 ].…”

“…The total protein concentration was measured with a Qubit fluorimetric protein assay (Thermo Fisher Scientific, Waltham, MA, USA). Forty micrograms of protein from each sample were digested with trypsin, and massive protein relative quantitation was conducted using the SWATH-MS approach, as previously described [ 72 ].…”

Neuronal and glial characterization in the rostrocaudal axis of the human anterior olfactory nucleus: Involvement in Parkinson’s disease

“…420782-9900); Iba-1, LBs, LNs, and overlapping areas; and GFAP, LBs, LNs, and overlapping areas (Plan Apochromat, 40X/0.95, Ref. in PD samples (Flores-Cuadrado et al, 2021;Villar-Conde et al, 2021). The total area fraction of different cell populations was calculated by the sum of markers with and without overlapping, except for AONb data in the NeuN study, which was obtained directly by quantification.…”

“…Parkinson’s disease is characterized by progressive neurodegeneration ( Poewe et al, 2017 ). Recently, neurodegeneration was reported in the human olfactory bulb ( Flores-Cuadrado et al, 2021 ), whereas it has not been reported in other brain areas, such as the hippocampus ( Villar-Conde et al, 2021 ). To date and to the best of our knowledge, only two studies have analyzed the neuronal population of AONb in PD.…”

Exercise-Boosted Mitochondrial Remodeling in Parkinson’s Disease

“…According to the prion hypothesis, α-synuclein spreads through neuronal connections and glia [ 111 ]. This propagation in the fourth stage of neuropathological course related to PD [ 112 ] reaches the hippocampus [ 113 ], producing changes in the proteins associated with synaptic structures and altering neuronal communication and function [ 114 ]. Owing to compensation and plasticity effects, during the progression of PD, training in daily living activities has been shown to restore neural circuits for movement, allowing intact nervous systems [ 115 ].…”