GAP-43 is a growth-associated
phosphoprotein expressed at high levels in neurons during development, axonal regeneration, and neuritic sprouting.
GAP-43 gene expression in mature neurons is probably functionally important for the structural remodeling of synapses as required for learning and establishing new memory. The widespread aberrant neuritic growth accompanied by impaired synaptic plasticity in
Alzheimer's disease (AD) suggests that abnormal
GAP-43 gene expression may contribute to the cascade of neurodegeneration. In the present study, end-stage AD brains exhibited reduced neuronal expression but increased glial cell levels of
GAP-43 mRNA and
protein. Glial cell localization of
GAP-43 gene expression was confirmed by in situ hybridization of cerebral tissue, Northern blot analysis of microdissected cerebral white matter, and independent analysis of
astrocytoma cell lines and primary malignant
astrocytomas. In addition, in AD,
GAP-43 immunoreactivity was translocated from the cytosol to membranes of swollen neuritic (dendritic) and glial cell processes throughout cerebral cortex and white matter. Downregulated and aberrant neuronal
GAP-43 gene expression appears to reflect an important molecular lesion that precedes and progresses with the widespread synaptic disconnection and
dementia in AD. At the same time, the presence of similar neuronal abnormalities in
Pick's disease,
diffuse Lewy body disease,
Parkinson's disease, and
Down syndrome suggests common mechanisms in the respective cascades of neurodegeneration. Finally, the finding of aberrantly increased glial cell
GAP-43 gene expression in AD exposes a previously unrecognized neurodegenerative change that may account for the axonal loss and white matter
atrophy detected early in the course of disease.