Astrocyte energy metabolism and neurotransmitter cycling in Alzheimer's disease

Vocabulary-style flashcards covering key concepts from the lecture on astrocyte energy metabolism and neurotransmitter cycling in Alzheimer's disease.

Glutamate/GABA-glutamine cycle

The neuron–astrocyte recycling loop that sustains excitatory and inhibitory neurotransmission by cycling glutamate, GABA, and glutamine between neurons and astrocytes.

Glutamine synthetase (GS)

Astrocytic enzyme that converts glutamate and NH4+ into glutamine; key for fixing ammonium and supplying neuronal glutamine; impaired in Alzheimer's disease.

Glutamate transporter EAAT2 (GLT-1)

Astrocyte-dense transporter responsible for the majority of synaptic glutamate uptake; loss or dysfunction can cause excitotoxicity.

Glutamate transporter EAAT1 (GLAST)

Astrocyte-associated transporter contributing to synaptic glutamate clearance alongside GLT-1.

GABA transporter GAT1

GABA transporter expressed in neurons and astrocytes that mediates GABA uptake; part of GABA clearance from the synapse.

GABA transporter GAT3

Astrocyte-predominant GABA transporter that clears GABA from the extracellular space.

SNAT1 (SLC38A1)

Neuronal sodium-coupled neutral amino acid transporter that transports glutamine into neurons.

SNAT3 (SLC38A3)

Astrocyte-expressed glutamine transporter critical for astrocyte-to-neuron glutamine transfer.

SNAT7/SNAT8

Neuronal glutamine transporters involved in intercellular glutamine handling.

Phosphate-activated glutaminase (PAG)

Converts glutamine to glutamate in neurons, supplying neurotransmitter glutamate for release.

Glutamate dehydrogenase (GDH)

Astrocyte-enriched enzyme that oxidatively deaminates glutamate to α-ketoglutarate; can fix ammonium under high NH4+ conditions and participate in glutamate metabolism.

Aspartate aminotransferase (AAT)

Transaminase linking glutamate to the malate–aspartate shuttle and TCA cycle; contributes to brain glutamate metabolism.

Glutamate decarboxylase (GAD)

Enzyme converting glutamate to GABA in GABAergic neurons.

GABA transaminase (GABA-T)

Enzyme that converts GABA to succinic semialdehyde (SSA) as part of GABA catabolism.

Succinic semialdehyde dehydrogenase (SSADH)

Converts SSA to succinate, feeding GABA-derived carbon into the TCA cycle.

Pyruvate carboxylase (PC)

Astrocyte-specific anaplerotic enzyme that carboxylates pyruvate to oxaloacetate, supporting de novo glutamine synthesis and TCA cycle function.

Anaplerosis

Replenishment of TCA cycle intermediates to sustain energy production and biosynthesis.

Astrocyte–neuron lactate shuttle (ANLSH)

Hypothesis that glial glycolysis (in response to neurotransmitter uptake) provides lactate to neurons as an oxidative fuel.

GLUT1 (glucose transporter 1)

Primary transporter for glucose into the brain; expression is reduced in cortex/hippocampus in AD, limiting glucose availability.

Hexokinase (HK) & Pyruvate kinase (PK)

Glycolytic enzymes; HK initiates glycolysis and PK is a key rate-limiting step; activity is reduced in AD astrocytes.

Glycolysis vs PPP in AD astrocytes

AD astrocytes show reduced glycolysis with compensatory upregulation of the pentose phosphate pathway to generate NADPH for antioxidant defense.

Pentose phosphate pathway (PPP)

Metabolic pathway producing NADPH and ribose-5-phosphate; upregulated in AD astrocytes to support antioxidant needs (e.g., glutathione synthesis).

β-hydroxybutyrate (βHB)

Ketone body used as an alternative brain energy substrate; elevated levels via diet may support neuronal energy when glucose metabolism is impaired.

Acetate metabolism in astrocytes

Astrocyte-preferring substrate entering the TCA cycle as acetyl-CoA; used to interrogate astrocyte metabolism and its changes in AD.

Monocarboxylate transporters (MCTs)

Transporters (e.g., MCT4) that move lactate, pyruvate, and ketone bodies across membranes; implicated in astrocyte metabolism and acetate handling in AD.

Pyruvate carboxylase (PC) flux in the hippocampus

Anaplerotic PC activity can account for a substantial fraction (~20%) of in vivo glucose oxidation in the awake hippocampus, linking energy metabolism to glutamine synthesis.

Astrocyte glycogen metabolism

Astrocyte-specific glycogen stores support energy supply for neurotransmission and glutamine synthesis; dysregulated in AD.

Aβ impact on GS & EAAT2

Amyloid-β can inhibit GS activity and reduce EAAT2 expression, impairing glutamate clearance and glutamine supply, contributing to excitotoxicity.

ApoE4 & astrocyte metabolism

APOE ε4 allele worsens astrocyte lipid handling and glucose metabolism, impairing neuron–astrocyte metabolic coupling in AD.

Astrocyte pathology in AD: astrogliosis vs atrophy

Astrocytes can become reactive (astrogliosis) with hypertrophy and GFAP upregulation, or undergo atrophy with loss of function; both affect neuronal support.

Clasmatodendrosis

Frag­ment­ation of astrocytic processes, a pathological change seen in ischemia, dementia, and neuroinflammation.

11C-DED PET tracer

Imaging marker for astrocyte reactivity; higher signals in MCI and changes with progression to AD.

11C-BU99008 PET tracer

Astrocyte reactivity imaging tracer used to study astrocyte function in aging and AD.

Ceftriaxone & EAAT2

Antibiotic shown to upregulate EAAT2 expression, boosting glutamate uptake and reducing excitotoxicity in AD models.

GABA release from astrocytes via MAO-B & Best1

Reactive astrocytes can synthesize GABA via MAO-B and release it through Best1 channels, contributing to tonic inhibition and memory impairment in AD.

GABA synthesis in astrocytes (GAD vs MAO-B pathways)

Astrocytes may produce GABA through MAO-B– or GAD-mediated pathways, influencing inhibitory signaling in AD.

SNAT3 expression changes in AD models

Altered glutamine transporter expression in astrocytes (e.g., SNAT3 downregulation) can limit astrocyte glutamine supply to neurons.

ammonium homeostasis & brain AD

Astrocyte GS-mediated ammonium fixation is challenged in AD; elevated brain ammonium is observed and may affect neurotransmitter metabolism.