Paula

When most authors still discuss and wonder whether the pathological process that underlies Parkinson’s disease starts either in neurons or in microglia so to target future therapies, one may suggest that initial alterations start in both, or, better, because of intimate relations between neurons and microglia, require impairements of both cellular groups and regulation to initiate and external factors to amplify.

Compared to inflammation in peripheral tissues, inflammation in brain appears to follow distinct pathways and time-courses, which likely has to do with a relatively strong immunosuppression in that organ.
The central nervous system appears to be a largely immunosuppressive environment, which previously led to the hypothesis that it is an "immunologically privileged" organ. Nevertheless, microglia can be activated by various internal and external stimuli, resulting in expression of cytokines and other mediators of inflammation. The molecular mechanisms converting those signals into specific microglial responses are a field of intensive research efforts.

It turns out that microglia are extremely sensitive towards any kind of stimulus. They are probably the first cells in the brain "sensing" changes in the periphery, and the summarized data suggest that microglia may even react in a specific manner in response to a specific stimulus.

Here starts the hypothesis of several previous “attacks” on brain neurons and microglia that lead to a special status of these cells, supporting reactions shifted during decades till reaching the point of illness trigger, with no spontaneous possibility to “go back to a healthy state and typical PD cells alterations characterized the formation of proteinaceous inclusions, Lewy bodies (LBs) and Lewy neurites (LNs)), lying in both neurons and microglia, and to a lower extend in astrocytes and oligodendrocytes.

The slowness of process may explain the appearent synucleopathy in PD which may "only" be sign of intra-cellular long term dysregulation, as well as taupathies when AD is concerned.

Different events probably exist or even co-exist with repeated hits on neurons and on microglia leading to mild chronicneuronal dysfunctions and microglia inflammatory reaction, until a point where illness really starts and autoentertains, and neuronal apoptosis begins under its own internal dysfunctions and microglia factors release of inflammatory cytokines as TNF-α , MHC II proteins, iNOS , COX-2, and components of complement.......


Reboot PD thinking, think it the dynamical way....

Anne

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