IMPACT OF D-SERINE DEPLETION IN THE β-AMYLOID CASCADERELATED TO ALZHEIMER’S DISEASE

International audienceD-serine, as a co-agonist of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR), is a key regulator of their activation and hence involves in functional brain plasticity and memory process. The homeostasis of these receptors is affected by soluble oligomers of the beta-amyloid peptide (Aß) in Alzheimer´s disease (AD). In the course of AD, early functional dysregulations of NMDAR are well known, even though contribution of D-serine remains so far to be determined. In 3-4 month-old transgenic mice model of amyloïdogenesis (5xFAD) showing marked increase in Aß rates and apparent unaffected D-serine levels, extracellular electrophysiological recordings reveal impaired NMDAR-dependent long-term potentiation at CA1/CA3 hippocampal synapses, without significant changes in basal synaptic transmission. This deficit persists at 12 month of age when amyloid deposits are present with concomitant disabilities in cognitive functions. Generating 5xFAD mice with depletion of D-serine (through invalidation of the synthesis enzyme: Serine Racemase), we observed that these functional alterations and the long-term behavioral impairment were prevented whereas Aßo rates remain significantly elevated and comparable to 5xAFD mice. Therefore, these results provide convincing evidence for a critical and transient involvement of D-serine in hippocampal network dysfunctions and related cognitive disabilities driven by increased amyloidogenesis

D-­‐SERINE IS INVOLVED IN THE β-­‐AMYLOID-­‐RELATED PATHOPHYSIOLOGYIN ALZHEIMER’S DISEASE

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The NMDA receptor activation by D-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of L-serine from glucose. Astrocytic L-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain D-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of L-and D-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular L-serine impaired LTP, supporting an L-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist D-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated D-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized D-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates D-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce D-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of D-serine metabolism and implicate both D-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism

Physiological and pathological roles of LRRK2 in the nuclear envelope integrity

Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson’s disease but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption. LRRK2 disease mutations mostly abolish the interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and leakage of nuclear proteins. Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 -/- mice display decreased circularity of the nuclear lamina and leakage of the nuclear protein 53BP1 to the cytosol. Dopaminergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormalities of the nuclear lamina. Our data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss of function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations

IMPACT OF D-SERINE DEPLETION IN THE β-AMYLOID CASCADERELATED TO ALZHEIMER’S DISEASE

International audienceD-serine, as a co-agonist of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR), is a key regulator of their activation and hence involves in functional brain plasticity and memory process. The homeostasis of these receptors is affected by soluble oligomers of the beta-amyloid peptide (Aß) in Alzheimer´s disease (AD). In the course of AD, early functional dysregulations of NMDAR are well known, even though contribution of D-serine remains so far to be determined. In 3-4 month-old transgenic mice model of amyloïdogenesis (5xFAD) showing marked increase in Aß rates and apparent unaffected D-serine levels, extracellular electrophysiological recordings reveal impaired NMDAR-dependent long-term potentiation at CA1/CA3 hippocampal synapses, without significant changes in basal synaptic transmission. This deficit persists at 12 month of age when amyloid deposits are present with concomitant disabilities in cognitive functions. Generating 5xFAD mice with depletion of D-serine (through invalidation of the synthesis enzyme: Serine Racemase), we observed that these functional alterations and the long-term behavioral impairment were prevented whereas Aßo rates remain significantly elevated and comparable to 5xAFD mice. Therefore, these results provide convincing evidence for a critical and transient involvement of D-serine in hippocampal network dysfunctions and related cognitive disabilities driven by increased amyloidogenesis

D-­‐SERINE IS INVOLVED IN THE β-­‐AMYLOID-­‐RELATED PATHOPHYSIOLOGYIN ALZHEIMER’S DISEASE

International audienc

A robust link between d-serine and amyloid pathology in a mouse model

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Neuronal D-Serine and Glycine Release Via the Asc-1 Transporter Regulates NMDA Receptor-Dependent Synaptic Activity

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