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.

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Animals were routinely perfusion‐fixed with 4% PFA in 0.1M PB (pH 7.4) under deep anesthesia as described (Alpár et al , 2014; Lendvai et al , 2013; Mulder et al , 2009; Romanov et al , 2015). …”

Astrocytes and extracellular matrix in extrasynaptic volume transmission

“…Aggrecan, cartilage link protein Crtl1 and tenascin-R have been identified as the main protective components of PNNs against iron-induced oxidative stress or Alzheimer's disease (AD) pathology [14,65]. The recent study of Lendvai et al [15] showed preserved ACs and increased brevican and Crtl1 expression in AD patients and transgenic APdE9 mice; this suggests an increased turnover of ECM molecules to maintain synaptic integrity.…”

“…The finding that ECM digestion increases performance in reversal learning without affecting already learned capacities brings forth the interesting challenge of guiding plastic changes using controlled ECM modulation [63]. On the other hand, mature PNNs and perisynaptic ACs create a protective shield attenuating the neurodegeneration evoked by neurotoxicity, oxidative stress or Ab deposits [14,15,65]. Aggrecan, cartilage link protein Crtl1 and tenascin-R have been identified as the main protective components of PNNs against iron-induced oxidative stress or Alzheimer's disease (AD) pathology [14,65].…”

“…While the model of a tripartite synapse [10], that suggests the cooperation of all three elements in signal transmission, is widely accepted, a more recent model introduces a fourth partner, the ECS-including its major component, the extracellular matrix (ECM) [9,11,12]. A condensed ECM surrounds the axosomatic synapses on interneurons forming aggrecanbased perineuronal nets (PNNs) [13], whereas other synapses can be covered by brevican-based axonal coats (ACs) [14,15]. 'Private'-or 'closed'-type synapses, tightly ensheathed by astrocytic processes and PNNs or ACs, prevail in the & 2014 The Author(s) Published by the Royal Society.…”

Secretagogin-dependent matrix metalloprotease-2 release from neurons regulates neuroblast migration

“…Chromogenic or multiple immunofluorescence histochemistry with select combinations of primary antibodies (Table S4) (1,34,35,49,51,(66)(67)(68)(69)(70)(71)(72)(73)(74) was performed according to published protocols (67). Results of chromogenic histochemistry were captured on an Olympus BX-51 microscope.…”