Bridging the Gap between Alzheimer's Disease and Alzheimer's-like Diseases in Animals.

The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer's disease (AD) is the most prevalent cause of progressive mental deterioration in aging humans, and there is a growing body of evidence that similar disorders (Alzheimer's-like diseases, ALD) are observed in animals, more than ever found in senescent individuals. This review reveals up to date knowledge in pathogenesis, hallmarks, diagnostic approaches and modalities in AD faced up with ALD related to different animal species. If found at necropsy, there are striking similarities between senile plaques (SP) and neurofibrillary tangles (NFT) in human and animal brains. Also, the set of clinical symptoms in ALD resembles that observed in AD. At molecular and microscopic levels, the human and animal brain histopathology in AD and ALD shows a great resemblance. AD is fatal, and the etiology is still unknown, although the myriad of efforts and techniques were employed in order to decipher the molecular mechanisms of disease onset and its progression. Nowadays, according to an increasing number of cases reported in animals, apparently, biochemistry of AD and ALD has a lot in common. Described observations point to the importance of extensive in vivo models and extensive pre-clinical studies on aging animals as a suitable model for AD disease.

Preliminary Study on Clusterin Protein (sCLU) Expression in PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish) AßPP genes Affected by Non-Steroid Isoprenoids and Water-Soluble Cholesterol.

In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AßPP) processing and regulates clusterin protein levels. AßPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor alpha (sAßPPα) presence in AßPP-wt cells and Aß expression in AßPP-sw cells. Nerve growth factor (NGF)-differentiated rat neuronal pheochromocytoma PC-12 cells were untreated/treated with statins alone or together with non-sterol isoprenoids. Co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol demonstrated statin-dependent neurotoxicity resulted from the attenuated activity of mevalonate pathway rather than lower cholesterol level. Atorvastatin (50 µM) or simvastatin (50 µM) as well as cholesterol chelator methyl-ß-cyclodextrin (0.2 mM) diminished cell viability (p < 0.05) and clusterin levels. Interestingly, co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol stimulated (p < 0.05) clusterin expression. Effects of non-sterol isoprenoids, but not water soluble cholesterol (Chol-PEG), were the most significant in mock-transfected cells. Geranylgeraniol (GGOH) overcame atorvastatin (ATR)-dependent cytotoxicity. This effect does not seem to be dependent on clusterin, as its level became lower after GGOH. The novelty of these findings is that they show that the mevalonate (MEV) pathway rather than cholesterol itself plays an important role in clusterin expression levels. In mock-transfected, rather than in AßPP-overexpressing cells, GGOH/farnesol (FOH) exerted a protective effect. Thus, protein prenylation with GGOH/FOH might play substantial role in neuronal cell survival.