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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias

Steffen Pockes1, Michael A Walters2, Karen H Ashe3

  • 1Institute of Pharmacy, University of Regensburg, Regensburg, Germany; Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota; Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

Translational Research : the Journal of Laboratory and Clinical Medicine
|November 7, 2022
PubMed

Insights

Targeting caspase-2 (Casp2) may offer new treatments for dementia. Casp2 cleavage of tau creates a protein fragment that disrupts neuron communication and synaptic function, suggesting Casp2 as a therapeutic target for neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Current Alzheimer's disease and related dementias (ADRD) treatments targeting amyloid-β plaques and tau tangles have shown limited efficacy.
  • Synaptic dysfunction and impaired neuronal communication are common pathological features across various neurodegenerative diseases with dementia.

Purpose of the Study:

  • To review the role of caspase-2 (Casp2) in a common signaling pathway implicated in dementia.
  • To highlight Casp2 as a druggable target for restoring synaptic function in ADRD.
  • To present initial medicinal chemistry efforts toward developing brain-penetrant Casp2 inhibitors.

Main Methods:

  • Review of existing scientific literature on Casp2, tau cleavage, and synaptic function in neurodegenerative diseases.
  • Characterization of the Casp2/tau/Δtau314 signaling pathway.
  • Overview of medicinal chemistry strategies for Casp2 inhibitor development.

Main Results:

  • Caspase-2 (Casp2) cleaves tau, producing a fragment (Δtau314) that promotes tau mislocalization to dendritic spines.
  • Δtau314 accumulation leads to AMPA receptor internalization and weakened synaptic transmission.
  • Evidence supports Casp2 as a critical mediator of synaptic dysfunction in ADRD.

Conclusions:

  • Caspase-2 (Casp2) represents a promising therapeutic target for Alzheimer's disease and related dementias (ADRD).
  • Inhibiting Casp2 may restore synaptic function and neuronal communication.
  • Further research into Casp2 inhibitors could lead to novel treatments for dementia.

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