The
calcium-activated protease calpain cleaves a variety of biologically important
proteins and serves, therefore, as a key regulator of many cellular functions. Activation of both main
isoforms,
calpain 1 and
calpain 2, was demonstrated previously in
Alzheimer's disease. In this report,
antibodies specifically recognizing the active form of
calpain 2 were used to investigate
calpain 2 activation in a broad range of
neurodegenerative diseases, utilizing multiple-label confocal immunofluorescence imaging. With rare exceptions, the active form of
calpain 2 was found in colocalization with hyperphosphorylated
tau protein. Aggregates of mutated huntingtin,
alpha-synuclein, or unidentified
protein in
motor neuron disease type of
frontotemporal dementia were always negative. These findings indicate that
calpain 2 activation is not a general response to
protein aggregation. In
tauopathies, more pathological inclusions were labeled for hyperphosphorylated tau than for activated
calpain 2. The extent of colocalization varied in both a disease-specific and cell-type specific manner. The active form of
calpain 2 was detected in 50-75% of tau neurofibrillary pathology in
Alzheimer's disease, Alzheimer neurofibrillary changes and
Down's syndrome, as well as in the accompanying Alzheimer-type tau pathology in diffuse Lewy bodies disease,
progressive supranuclear palsy, and
corticobasal degeneration. For glial cells, only 10-25% of tuft-shaped astrocytes, glial plaques, or coiled bodies contained activated
calpain 2. The majority of Pick bodies were negative. The association of
calpain 2 activation with hyperphosphorylated tau might be the result of an attempt by the
calpain proteolytic system to degrade the
tau protein aggregates. Alternatively,
calpain 2 could be directly involved in tau hyperphosphorylation by modulating
protein kinase activities. Overall, these results provide evidence of the important role of the
calpain proteolytic system in the pathogenesis of
neurodegenerative diseases with tau neurofibrillary pathology.