The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia

Walter J Schulz-Schaeffer, Walter J Schulz-Schaeffer

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter deficiency. Recently it was shown that 90% or even more of alpha-synuclein aggregates in DLB cases were located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting a neurotransmitter deprivation. The same alpha-synuclein pathology can be demonstrated for PD. These findings give rise to the notion that not cell death but rather alpha-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration. This opens new perspectives for understanding PD and DLB. If presynaptic alpha-synuclein aggregation, not neuronal loss, is the key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration of synapses.

Figures

Fig. 1
Fig. 1
Detection of α-synuclein deposits in DLB with conventional methods. H&E (a) shows 3 Lewy bodies (arrows). Immunohistochemically, Lewy bodies are detectable (b), whereas in the neuropil α-synuclein deposits are not distinguishable from the physiological α-synuclein staining (d) as compared to a control case (mAB 4B12, 1:1,000, abcam). With an antibody against phosphorylated α-synuclein (c), more deposits than just Lewy bodies are detectable (polyAB pSer129, 1:500, LifeSpan BioScience). Bar 100 μm
Fig. 2
Fig. 2
More than 90% of α-synuclein aggregates are located outside of Lewy bodies at synapses in the frontal cortex of DLB. Frontal cortex and cingulate gyrus of a DLB- and control patient as seen using a dissection microscope (a, b). The higher magnification of the PET blot (c) shows the synaptic distribution of aggregates much smaller than Lewy bodies (LB indicated by arrows; mAB 4B12, 1:10,000). Using an antibody against phosphorylated α-synuclein (d), only a fraction of proteinase K-resistant aggregates is detectable (polyAB pSer129, 1:5,000). The detectability of phosphorylated α-synuclein is strongly influenced by the fixation period. Here the tissue was fixated short term using buffered formaldehyde. Bar 100 μm
Fig. 3
Fig. 3
Synaptic α-synuclein aggregates are the main synuclein pathology in Parkinson’s disease as seen in DLB. The substantia nigra shows several proteinase K-resistant α-synuclein aggregates besides Lewy bodies (a). In a Parkinson’s disease patient with dementia (b), the frontal cortex shows a lot of tiny α-synuclein aggregates even though no Lewy bodies are detectable (mAB 4B12, 1:10,000). Bar 100 μm
Fig. 4
Fig. 4
An almost complete loss of dendritic spines accompanies the presynaptic α-synuclein aggregates. Golgy–Cox–Davenport staining of a neuronal dendrite of a frontal cortex neuron in a DLB patient (a) is compared to a control patient of the same age (b). Bar 50 μm

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