Transglutaminase and its role in Alzheimer's disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics

Alzheimer's disease (AD) involves more than just the well-known amyloid plaques and tau tangles — mitochondria, the cell's energy factories, also break down in ways that accelerate neuronal death. This review focuses on an enzyme called transglutaminase 2 (TG2), which is normally involved in protein crosslinking and cellular repair but goes haywire in the aging brain. When TG2 becomes overactive, it glues together amyloid and tau proteins into more toxic clumps, and simultaneously damages mitochondria by altering key proteins that control energy production and calcium balance. Critically, TG2 also sabotages the cell's waste-disposal system for damaged mitochondria — a process called mitophagy — by chemically modifying PINK1 and Parkin, two proteins essential for flagging and removing dysfunctional mitochondria. Aging itself worsens the situation, because rising oxidative stress and inflammation both switch TG2 on further, creating a vicious cycle. Metabolomics data reviewed here also show that TG2 disrupts lipid and amino acid pathways that neurons depend on for fuel and signaling. The authors argue that selectively blocking TG2's crosslinking activity — while leaving its other cellular jobs intact — could be a viable strategy for slowing AD progression.

• TG2 catalyzes ε-(γ-glutamyl)-lysine crosslinks that stabilize and enlarge both amyloid-β plaques and tau neurofibrillary tangles, making these aggregates harder for cells to clear.
• Aberrant TG2 activity modifies VDAC and ANT1 — two proteins embedded in the mitochondrial membrane — disrupting calcium homeostasis and bioenergetic efficiency, ultimately triggering apoptosis.
• TG2 crosslinks PINK1 and Parkin, impairing the mitophagy pathway responsible for removing damaged mitochondria; selective TG2 inhibition in preclinical models restores autophagic flux and reduces aggregate burden.
• Metabolomic analyses indicate that TG2-driven dysregulation extends to lipid and amino acid metabolism, compounding mitochondrial respiratory deficits and disrupting neuronal signaling networks.
• Aging-associated increases in reactive oxygen species (ROS) and pro-inflammatory cytokines further amplify TG2 activation, establishing a feed-forward loop between proteostatic collapse, synaptic degeneration, and mitochondrial failure.

This is a narrative integrative review (no original patient data or animal experiments are reported), synthesizing published preclinical studies, biochemical assays, and metabolomic datasets that collectively examine TG2's mechanistic roles in AD pathology. The authors draw on in vitro neuronal models, transgenic AD mouse studies, and human metabolomics cohorts identified through a systematic literature search. No specific sample sizes or follow-up periods apply, as the work aggregates findings across heterogeneous source studies rather than reporting a single trial or experiment.

As a narrative review, this article cannot establish causality or quantify effect sizes independently — conclusions depend on the quality and reproducibility of the underlying primary studies, which vary considerably in model systems and TG2 inhibitor specificity. All therapeutic evidence cited comes from preclinical (cell culture and rodent) models, leaving the translational relevance to human AD unconfirmed. The review does not perform a formal meta-analysis or systematic risk-of-bias assessment, so publication bias in the source literature is unaddressed. The key next experiment would be a longitudinal study in a humanized AD model using a selective TG2 transamidase inhibitor, measuring mitophagy flux, mitochondrial respiration, and cognitive outcomes in parallel to determine whether TG2 inhibition is sufficient — not merely correlative — for neuroprotection.

This review extends [§27] and [§48], which together demonstrate that astrocyte-to-neuron mitochondrial transfer is disrupted in AD via the CD38-Miro1 axis — a complementary upstream failure that TG2-mediated mitophagy blockade would compound by simultaneously preventing neurons from degrading their own damaged mitochondria. It parallels [§99], which identifies mitochondrial RNA release during aging as a driver of inflammation and senescence, consistent with the feed-forward ROS-TG2 activation loop described here. The mechanistic focus on PINK1/Parkin crosslinking directly contextualizes [§134], where BMAL1 deficiency heightens PINK1/Parkin-linked mitophagy in cardiomyocytes, illustrating that dysregulation of this same pathway drives pathology across tissue types. Collectively, these articles reinforce a corpus-wide theme that mitophagy integrity is a nodal vulnerability in age-related disease, with TG2 representing a disease-specific enzymatic amplifier in the neurodegeneration context.

• Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer’s Disease: Mechanisms and Therapeutic Restoration
  Directly parallel AD-mitochondria study — examines CD38-Miro1-mediated astrocyte-neuron mitochondrial transfer failure in AD, offering a complementary intercellular mechanism to TG2's intraneuronal mitophagy blockade.
• Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration
  Earlier version of the CD38-Miro1 AD article; comparing both [id=27] and [id=48] against this review clarifies whether extracellular mitochondrial rescue can compensate for TG2-driven intracellular mitophagy failure.
• Mitigating Mitochondrial RNA Release During Aging to Control Inflammation and Senescence
  Investigates mitochondrial RNA release as an aging-linked inflammatory trigger — mechanistically upstream of the ROS-inflammation-TG2 activation cycle reviewed here, making it a useful entry point for the aging angle.
• Cardiomyocyte BMAL1 deficiency worsens obesity-related cardiomyopathy with heightened PINK1/Parkin-linked mitophagy and mitochondrial dysfunction
  Demonstrates that PINK1/Parkin-linked mitophagy becomes dysregulated in BMAL1-deficient cardiomyocytes, providing a non-neuronal comparator for assessing how context-specific TG2's crosslinking of these same proteins is in AD.
• Placebo-Controlled Trial of Urolithin A Supplementation in Men With Prostate Cancer Undergoing Radical Prostatectomy, URO-PRO Trial
  Placebo-controlled trial of urolithin A — a mitophagy activator — in humans; offers direct translational context for whether pharmacologically restoring mitophagy flux (the therapeutic goal of TG2 inhibition) produces measurable clinical benefit.