Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Abeta triggers neurodegeneration, in DLB accumulation of alpha-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Abeta and alpha-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.