George Marinesco in the Constellation of Modern Neuroscience

Alzheimer's disease (AD) is associated with dementia, brain atrophy and the aggregation and accumulation of a cortical amyloid-beta peptide (Abeta). Chronic bacterial infections are frequently associated with amyloid deposition. It had been known from a century that the spirochete Treponema pallidum can cause dementia in the atrophic form of general paresis. It is noteworthy that the pathological hallmarks of this atrophic form are similar to those of AD. Recent observations showed that bacteria, including spirochetes contain amyloidogenic proteins and also that Abeta deposition and tau phosphorylation can be induced in or in vivo following exposure to bacteria or LPS. Bacteria or their poorly degradable debris are powerful inflammatory cytokine inducers, activate complement, affect vascular permeability, generate nitric oxide and free radicals, induce apoptosis and are amyloidogenic. All these processes are involved in the pathogenesis of AD. Old and new observations, reviewed here, indicate that to consider the possibility that bacteria, including several types of spirochetes highly prevalent in the population at large or their persisting debris may initiate cascade of events leading to chronic inflammation and amyloid deposition in AD is important, as appropriate antibacterial and antiinflammatory therapy would be available to prevent dementia.

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. Although aging is a primary risk factor for PD, its role in DA neuron degeneration remains unknown. Neurodegeneration in PD is not uniform throughout the ventral midbrain: the ventral tier of the substantia nigra (vtSN) is most vulnerable, whereas the dorsal tier (dtSN) and ventral tegmental area (VTA) are relatively resistant. We studied young (9-10 years old), middle-aged (14-17 years old), and old-aged (22-29 years old) rhesus monkeys to identify factors potentially underlying selective vulnerability and their association with aging. We focused on markers relevant to the ubiquitin-proteasome (UPS) and lysosome systems. Unbiased stereological counting was performed on tyrosine hydroxylase-positive (TH+) neurons and TH+ neurons containing Marinesco bodies (TH+MB) or lipofuscin (TH+lipo), markers of UPS or lysosomal activity, respectively. TH+ neuron numbers were inversely correlated with advancing age specifically in the vtSN, not the dtSN or VTA. TH intensity decreased throughout the ventral midbrain with increasing age, an effect exacerbated in the vtSN. TH+MB neurons were localized in the vulnerable vtSN of old monkeys. The number of MBs per cell increased with age, and TH intensity of TH+MB neurons decreased in middle age. Conversely, TH+lipo neurons were primarily found in the resistant dtSN and VTA. These data suggest that particular age-related changes localize to DAergic subregions relevant to degenerative patterns in PD. Furthermore, the results begin to characterize the nature of the link between aging and PD, and they support the concept that aged monkeys represent a valuable model for studying specific events preceding PD.