title: Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease.
abstract: Perineuronal matrix is an extracellular protein scaffold to shape neuronal responsiveness and survival. Whilst perineuronal nets engulf the somatodendritic axis of neurons, axonal coats are focal extracellular protein aggregates surrounding individual synapses. Here, we addressed the chemical identity and subcellular localization of both perineuronal and perisynaptic matrices in the human hippocampus, whose neuronal circuitry is progressively compromised in Alzheimer's disease. We hypothesized that (1) the cellular expression sites of chondroitin sulphate proteoglycan-containing extracellular matrix associate with specific neuronal identities, reflecting network dynamics, and (2) the regional distribution and molecular composition of axonal coats must withstand Alzheimer's disease-related modifications to protect functional synapses. We show by epitope-specific antibodies that the perineuronal protomap of the human hippocampus is distinct from other mammals since pyramidal cells but not calretinin(+) and calbindin(+) interneurons, neurochemically classified as novel neuronal subtypes, lack perineuronal nets. We find that cartilage link protein-1 and brevican-containing matrices form isolated perisynaptic coats, engulfing both inhibitory and excitatory terminals in the dentate gyrus and entorhinal cortex. Ultrastructural analysis revealed that presynaptic neurons contribute components of perisynaptic coats via axonal transport. We demonstrate, by combining biochemical profiling and neuroanatomy in Alzheimer's patients and transgenic (APdE9) mice, the preserved turnover and distribution of axonal coats around functional synapses along dendrite segments containing hyperphosphorylated tau and in amyloid-β-laden hippocampal microdomains. We conclude that the presynapse-driven formation of axonal coats is a candidate mechanism to maintain synapse integrity under neurodegenerative conditions.
authors.affiliation: Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Lendvai
authors.forename: Markus
authors.initials: M
authors.lastname: Morawski
authors.forename: László
authors.initials: L
authors.lastname: Négyessy
authors.forename: Georgina
authors.initials: G
authors.lastname: Gáti
authors.forename: Carsten
authors.initials: C
authors.lastname: Jäger
authors.forename: Gábor
authors.initials: G
authors.lastname: Baksa
authors.forename: Tibor
authors.initials: T
authors.lastname: Glasz
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Thomas
authors.initials: T
authors.lastname: Arendt
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001369:Axons / Q000378:metabolism; D015153:Blotting, Western; D001931:Brain Mapping; D058581:Brevican / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015331:Cohort Studies; D003712:Dendrites / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D011509:Proteoglycans / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D050481:Vesicular Neurotransmitter Transport Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism; D000099249:Proteoglycan Link Protein
chemical_list: D053674:Aggrecans; D016229:Amyloid beta-Peptides; D058581:Brevican; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D050481:Vesicular Neurotransmitter Transport Proteins; D016875:tau Proteins; D000099249:Proteoglycan Link Protein