| Autor: |
Bell BJ; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States., Malvankar MM; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States., Tallon C; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States., Slusher BS; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States. |
| Abstrakt: |
The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo . Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials. |
