RETRACTED: Wild type and P301L mutant Tau promote neuro-inflammation and α-Synuclein accumulation in lentiviral gene delivery models

Abstract

Neurodegeneration involves multiple pathogenic proteins, including Tau, Aβ, TDP-43 and α-Synuclein, but there is little information how these pathogenic proteins interact. We cloned human wild type 4 repeat Tau (Tauwt) and mutant TauP301L into a lentivirus and performed stereotaxic injection into the rat motor cortex to examine Tau modification, neuro-inflammation and changes of other proteins associated with neurodegeneration. TauP301L was associated with more phosphorylation of Tau, including Thr 181 and Ser 262 residues and resulted in more aggregation. Both forms of Tau expression increased glycogen synthase kinase-3 (GSK-3) activity, polo-like kinase-2 (PLK2) levels and decreased protein phosphatase activity, but had no effects on casein kinase-1 (CK1). No changes were observed in glial fibrillary acidic protein (GFAP) staining with either Tauwt or TauP301L, but both caused microglial changes and higher interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Tauwt and TauP301L increased the levels of endogenous α-Synuclein, but not β-amyloid precursor protein (βAPP) or Tar-DNA binding protein (TDP-43). The levels of phosphorylated Ser-129 α-Synuclein (p-Ser129) were also increased with Tauwt and TauP301L expressing animals. These data suggest that Tauwt and TauP301L alter kinase activities, but they differentially induce inflammation, Tau modification and α-Synuclein phosphorylation. This change of α-Synuclein in Tau gene transfer models suggests that Tau pathology may lead to α-Synuclein modification in neurodegenerative diseases.

Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease

“…The current data suggest that amyloid accumulation results in Tau modification (Khandelwal et al, 2010, Rebeck et al, 2010) and protein aggregation similar to over-expression of Tau (Khandelwal et al, 2011a) or Aβ 1–42 (Lonskaya et al, 2012). Accumulation of autophagosomes in neurodegeneration may be due to reduced autophagic flux (Gonzalez-Polo et al, 2005).…”

Alpha-synuclein and tau: teammates in neurodegeneration?

“…For instance, in rats, αsyn overexpression induced by stereotaxic injection of lentivirus increases phospho-tau levels [94]. On the contrary, rats transduced with tau and mutant P301L tau display an increase of αsyn and phospho-αsyn levels [95]. In another study using adeno-associated vectors for gene transfer into the substantia nigra of rats, overexpression of human wt and P301L tau, but not αsyn, provoked dopaminergic neurodegeneration, reduced striatal dopamine content, and motor deficit as measured by amphetamine-stimulated rotational behavior [96].…”

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

“…Based on immunostaining, the APP23 transgenic mice displayed increased tau phosphorylation and aggregation compared to the wild-type mice also injected with lenti-P301S. Another group found that P301L tau expression caused an increase in tau phosphorylation, tau aggregation, and activated microglia when compared to wild-type tau expression in the rat motor cortex rats [130]. Lentivirus expression of wild-type or P301L tau in the rat HP produced a progressive appearance of dystrophic and fragmented neurites prior to the formation of NFT-like inclusions that developed over 8 months [131].…”