Fig. 6

Schematic drawing of proteinopathy and axonal degeneration in the anterior insula in PD, PDD and DLB. The neuron, its axon, axonal cytosketon, myelin, and supportive cells such as astrocytes are all involved in the degenerative process in PD, PDD and DLB with more severe features in DLB. Astrocytes are reactive and take up α-synuclein deposits ending in their degeneration. The axon is affected at multiple levels; it contains α-synuclein deposits (LBs and LNs) which impede axonal transport. Neurofibrillary tangles (NFT) contain hyperphosphorylated tau (p-tau) that begins as pre-tangles and matures into ghost tangles. The hyperphosphorylation and accumulation of p-tau impairs the axonal cytoskeleton and leads to depolymerization of the microtubule. p-Tau and α-synuclein can also stimulate each other’s aggregation, speeding up degeneration. Amyloid-β plaques, which are more severe in the dysgranular insula, contribute to impaired cellular trafficking and myelin instability. Amyloid-β deposits in and surrounding blood vessels, CAA, lead to poor clearance of abnormal proteins and blood–brain barrier dysfunction. Finally, myelinated axons are also affected through axon-myelin unit detachment and demyelination, which affects conduction velocity and axonal support. All together, axonal length, integrity and cellular trafficking become impaired in the anterior insular subregions in PD, PDD and most severe in DLB donors with consequent impairment of insular functions as a brain hub and emotional/cognitive deficits as a result. CAA: cerebrovascular amyloid angiopathy; DLB: Dementia with Lewy bodies; LB: Lewy body; LN: Lewy neurite; PD: Parkinson’s disease; p-tau: hyperphosphorylated tau