Alzheimer’s and Parkinson’s diseases are the most prevalent neurodegenerative disorders. Their etiologies are idiopathic, and treatments are symptomatic and orientated towards cognitive or motor deficits. Neuropathologically, both are proteinopathies with pathological aggregates (plaques of amyloid-β peptide and neurofibrillary tangles of tau protein in Alzheimer’s disease, and Lewy bodies mostly composed of α-synuclein in Parkinson’s disease). These deposits appear in the nervous system in a predictable and accumulative sequence with six neuropathological stages. Both disorders present a long prodromal period, characterized by preclinical signs including hyposmia. Interestingly, the olfactory system, particularly the anterior olfactory nucleus, is initially and preferentially affected by the pathology. Cerebral atrophy revealed by magnetic resonance imaging must be complemented by histological analyses to ascertain whether neuronal and/or glial loss or neuropil remodeling are responsible for volumetric changes. It has been proposed that these proteinopathies could act in a prion-like manner in which a misfolded protein would be able to force native proteins into pathogenic folding (seeding), which then propagates through neurons and glia (spreading). Existing data have been examined to establish why some neuronal populations are vulnerable while others are resistant to pathology and to what extent glia prevent and/or facilitate proteinopathy spreading. Connectomic approaches reveal a number of hubs in the olfactory system (anterior olfactory nucleus, olfactory entorhinal cortex and cortical amygdala) that are key interconnectors with the main hubs (the entorhinal–hippocampal–cortical and amygdala–dorsal motor vagal nucleus) of network dysfunction in Alzheimer’s and Parkinson’s diseases.

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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.

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC >1.5 and p value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy.

Introduction:The entorhinal cortex is among the earliest areas involved in Alzheimer's disease. Volume reduction and neural loss in this area have been widely reported.Human entorhinal cortex atrophy is, in part, due to neural loss, but microglial and/or astroglial involvement in the different layers remains unclear. Additionally, -omic approaches in the human entorhinal cortex are scarce.Methods: Herein, stereological layer-specific and proteomic analyses were carried out in the human brain.Results: Neurodegeneration, microglial reduction, and astrogliosis have been demonstrated, and proteomic data have revealed relationships with up-(S100A6, PPP1R1B, BAG3, and PRDX6) and downregulated (GSK3B, SYN1, DLG4, and RAB3A) proteins.Namely, clusters of these proteins were related to synaptic, neuroinflammatory, and oxidative stress processes. Discussion: Differential layer involvement among neural and glial populations determined by proteinopathies and identified proteins related to neurodegeneration and astrogliosis could explain how the cortical circuitry facilitates pathological spreading within the medial temporal lobe.