Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia

Abstract

Background: Proteinopathies are a heterogenous group of neurodegenerative disorders, characterized by intra- and extracellular accumulation of abnormal filament proteins.

Objective: To describe the neuropathology of specific forms of tauopathies and synucleinopathies, the overlap of morphologic features and molecular interactions.

Methods: The study uses currently available morphologic criteria of different proteinopathies.

Results: Alzheimer disease (AD) is featured by deposition of beta-amyloid peptides, phosphorylated tau protein (3- and 4-repeat tau) and frequent alpha-synuclein (aSyn) deposits. Lewy body diseases (LBD), such as sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), show aSyn-positive deposits in neurons, neurites, glia, and presynaptic terminals, while frontotemporal dementias present tau-positive and tau-negative, ubiquitin- and TDP-43-positive neuronal and glial inclusions. The latter have also been observed in AD, PD, PD dementia and motor neuron disorders. Molecular interactions between major proteins, which may occur within the same brain in various distribution patterns, cause variable phenotypes and mixed pathologies, e.g. AD with aSyn pathology in the brainstem and amygdala, PD and DLB with AD lesions, and frontotemporal dementia with a mixture of various deposits, while others are featured by one principal pathology without other lesions (e.g. tangle-predominant type of dementia, pure PD, brainstem-predominant LBD).

Conclusion: Animal models and in vitro studies showing co-occurrence and mutual promotion of fibrillation of these proteins indicate their synergistic interactions in the pathogenesis of these disorders which, at least in part, are genetically influenced.