Some aged community dogs acquire a degenerative syndrome termed Canine Cognitive Dysfunction (CCD) that resembles human dementia because of Alzheimer’s Disease (AD), with comparable cognitive and behavioral deficits. Dogs also have similar neuroanatomy, share our domestic environment and develop amyloid‐β plaques, making them likely a valuable ecological model of AD. However, prior investigations have demonstrated a lack of neurofibrillary tau pathology in aged dogs, an important hallmark of AD, though elevated phosphorylated tau (p‐tau) at the Serine 396 (S396) epitope has been reported in CCD. Here using enhanced immunohistochemical methods, we investigated p‐tau in six CCD brains and six controls using the AT8 antibody (later stage neurofibrillary pathology), and an antibody against S396 p‐tau (earlier stage tau dysfunction). For the first time, we systematically assessed the Papez circuit and regions associated with Braak staging and found that all CCD dogs displayed elevated S396 p‐tau labeling throughout the circuit. The limbic thalamus was particularly implicated, with a similar labeling pattern to that reported for AD neurofibrillary pathology, especially the anterior nuclei, while the hippocampus exhibited dysfunction confined to synaptic layers and efferent pathways. The cingulate and temporal lobes displayed significantly greater tauopathy than the frontal and occipital cortices, also reflective of early Braak staging patterns in AD. Immunofluorescence confirmed that S396 was accumulating within neuronal axons, somata and oligodendrocytes. We also observed AT8 labeling in one CCD brain, near the transentorhinal cortex in layer II neurons, one of the first regions to be affected in AD. Together, these data demonstrate a concordance in regional distribution of tauopathy between CCD and AD, most evident in the limbic thalamus, an important step in further validating CCD as a translational model for human AD and understanding early AD pathogenic mechanisms.
Alzheimers-disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-beta (A beta) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that A beta-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unstudied. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant A beta were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. We found axonal transport of mitochondria, mitochondrial function, and cortical neuron differentiation propensity remained unaffected regardless of tau expression levels. Finally, tau depletion protected neurons from adverse effects mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in A beta-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt-/- mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Background Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. Methods A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. Results Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. Conclusions With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.
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