Human neurodegenerative diseases comprise a heterogenous group of disorders, underpinned by complex interactions of cell-intrinsic and -extrinsic molecular mechanisms between multiple different neuronal and non-neuronal cell types. Understandably, the spatio-temporal isolation and investigation of specific pathogenic mechanism remain largely nebulous, and effective and efficacious disease-modifying therapies remain elusive.
While the ordered assembly and accumulation of the microtubule-associated Tau protein into abnormal filamentous inclusions is the most common pathology among many neurodegenerative diseases, including Alzheimer's disease2, mechanisms underlying tau-mediated neurotoxicity are poorly understood.
Tauopathies and Neurodegenerative DiseasesIt has been previously reported that the accumulation of tau-containing neurofibrillary tangle (NFT) correlates closely with cognitive decline and cell loss in AD patients3. However, NFT formation does not induce programmed cell death (PCD) per se4, which suggests alternative non-PCD neurotoxic mechanisms are at play.
Musi and co-workers employed different experimental modalities to further interrogate this cellular phenomenon. First, they performed transcriptomic analyses of post-mortem brain samples from human patients with NFT pathologies and uncovered the up-regulation of cellular senescence-associated gene pathways. Since mutations in the gene (Mtapt) encoding Tau protein, the most common being (P301L), causes familial forms of frontotemporal dementia5 the authors recapitulated the transcriptomic profile in the brains of aged rTg(tauP301L)4510 mice (tauNFT, two-to-six months of age), but not those from rTg(tauWT)21221 mice (named tauWT). These transgenic animals either express human mutant tau P301L or merely overexpresses human wild type tau 4R02 proteins, respectively.
The tauWT mice acquire age-dependent tau-associated pathologies, albeit at a slower rate compared to the tauNFT, and have often been used to identify effects of elevated pre-pathogenic tau6,7. Since cellular senescence is a complex stress response, the authors were able to further identify activation of DNA damage (such as Cdkn1a and Cdkn2a); chronic tissue degeneration through secretion of toxic SASP, as well as aberrant mitochondrial bioenergetics in tauNFT murine brains.
Therapeutic Insights from Connecting Senescence and TauopathySubsequently, Musi and co-workers employed multiple genetic approaches by crossing these transgenic mice with other GEM ageing models:
After validating the up-regulation of CDKN2A in human brains with histopathologically-confirmed tauopathy, Musi and co-workers utilised senolytics (Dasatinib and Quercitin) to remove senescent cells in the brains of advanced age (twenty to twenty-three months) tauNFT-Mapt-/- and non-transgenic-Mapt-/-.
The pharmacological treatment with Quercitin resulted in significant long-lasting global benefits on cerebral blood flow and neurodegeneration, evident by reduction of AD-associated histopathological and radiological signs (reduction in cortical NFT burden, brain atrophy, neuron loss, and ventricular enlargement).
Increasing literature supports the heterogeneous pathophysiologies underlying neurodegenerative diseases such as Alzheimer's disease, with contributions from the environment and the microbiome. Musi and co-workers combined multiple animal models (genetic modifications with aging) to provide an insight into the association between cellular senescence and tauopathy, as well as a novel therapeutic strategy.
Taconic's Neuroscience Animal ModelsTaconic Biosciences' transgenic Tau model Tg(Prnp-MAPT*P301L) develops age-related neuropathologies similar to the transgenic tauNFT mouse utilised by Musi et al. However, the former expresses either human P301L or wild-type Mapt cDNA under the heterologous mouse prion promoter (MoPrP). The Tg(Prnp-MAPT*P301L) phenocopies human tauopathies with behavioral and motor disturbances related to development of neurofibrillary tangles (NFT).
These signs and symptoms develop as early as 4.5 and 6.5 months in homozygous and hemizygous animals respectively, followed by gliosis and changes in long-term potentiation and depression at nine months.
The significance of these findings are: neurofibrillary pathology that is linked to neuronal loss allow the interrogation of critical events in tau-mediated neurodegeneration; murine models to study the relationship of NFT with other related pathologies such as Aβ proteinopathies in Taconic's combined Tg(APPSWE)2576Kha Tg(Prnp-MAPT*P301L) transgenic mouse. Since the hallmarks of AD are Aβ plaques, NFT tangles, and cognitive deficits, Taconic's neuroscience portfolio provides a variety of validated transgenic murine models that facilitates the screening of novel drug candidates for treating AD and other neurodegenerative diseases.