Welcome to the AD/PD™ 2021 Interactive Program
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- Live Session | 
- On Demand Session | 
- On Demand with Live Q&A
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FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.
SYNAPTIC DENSITY VERSUS TAU ACCUMULATION IN PRIMARY TAUOPATHIES: A NEGATIVE CORRELATION MODERATED BY DISEASE SEVERITY.
Abstract
Aims
The relationship between synaptic loss and tau accumulation in human tauopathies remains to be elucidated in vivo. There is widespread synaptic loss in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD: amyloid-negative corticobasal syndrome (CBS)) (Holland et al. Mov Disord. 2020).
Methods
We determine how synaptic loss correlates with tau accumulation, using [11C]UCB-J and [18F]AV1451 PET, respectively. Fifteen patients with PSP (m:f 7:8, age ± sd: 71 ± 9.8), fifteen with corticobasal syndrome (9 amyloid negative; m:f 7:2, age ± sd: 70.9 ± 8.2) and fifteen age-/sex-/education-matched healthy controls (m:f 7:8, age ± sd: 68.5 ± 7.5) were recruited. All participants had a neuropsychological battery and a 3T MRI. Patients with CBS also had amyloid PET with [11C]PiB to exclude those with likely Alzheimer’s pathology.
Results
We show that there is a negative correlation between [11C]UCB-J and [18F]AV1451 binding potentials both within regions (pallidum & hippocampus, p<0.05), and between widespread areas of the cortex and striatum. Between-subjects’ variability in the slope of the correlation was related to patients’ disease severity as measured with the PSP rating scale ((F(2,21)=4.13, beta= -0.008, p= <0.01).
Conclusions
We confirm a negative correlation between synaptic density and tau accumulation, moderated by disease severity, however longitudinal imaging is required to estimate the mediation of synaptic loss by tau accumulation. Given the importance of synaptic density for neurocognitive function, our study not only elucidates the pathophysiology of primary tauopathies but also informs the design of clinical trials at different stages of disease.
PATHOLOGICAL TAU INDUCES NEURODEGENERATION BY SEQUESTERING AND INHIBITING LSD1
Abstract
Aims
Alzheimer’s disease (AD) is characterized by the aberrant accumulation of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau (NFTs). Surprisingly, we previously found that the histone demethylase LSD1/KDM1A is mislocalized to NFTs in AD cases. In addition, we showed that loss of LSD1 systemically in adult mice is sufficient to recapitulate many aspects of AD, including widespread neuronal cell death in the hippocampus and cortex, learning and memory defects, and global gene expression changes that match AD cases. Based on these data, we sought to determine whether pathological tau functions through LSD1 to induce neuronal dysfunction.
Methods
If pathological tau is functioning through the sequestration of LSD1, then reducing LSD1 in PS19 Tauopathy mice should make these mice more sensitive to pathological tau, and overexpressing LSD1 should rescue neuronal dysfunction.
Results
Reducing LSD1 in PS19 Tau mice accelerates the depletion of LSD1 from the nucleus. This results in decreased survival, exacerbated paralysis, and increased neurodegeneration. Reducing LSD1 also exacerbates the genome-wide expression changes induced by pathological tau. Conversely, overexpressing LSD1 in hippocampal neurons of PS19 mice at 8.5 months, when pathological tau is already present, is sufficient to suppress tau-induced neurodegeneration and block the Tau induced immune response through 11 months. In addition, overexpressing LSD1 specifically counteracts tau-induced gene expression changes genome-wide.
Conclusions
We propose that pathological tau leads to neuronal cell death in AD by sequestering LSD1 in the cytoplasm and interfering with the continuous requirement for LSD1 to epigenetically repress transcription associated with alternative cell fates.
ENTORHINAL CORTEX WOLFRAMIN-1-EXPRESSING NEURONS PROPAGATE TAU TO CA1 NEURONS AND IMPAIR HIPPOCAMPAL MEMORY
Abstract
Aims
In early stages of Alzheimer’s Disease (AD), phosphorylated tau propagates from layer II of the entorhinal cortex (ECII) to the CA1 in the hippocampus. Wolframin-1-expressing (Wfs1+) pyramidal neurons in ECII connect to the CA1 region via temporo-ammonic pathway. We hypothesized that Wfs1+neurons in ECII mediate tau propagation to the CA1 and mimic early stages of tau pathology in AD.
Methods
Wfs1-Cre mice at 4-6 months of age were injected with Cre-inducible AAV2/6-Flex-P301Ltau expressing human P301L tau mutant or AAV2/6-Flex-TdTomato in ECII to specifically express mutant tau in Wfs1+ neurons. At 4 weeks post-injection, the mice were euthanized for immunohistochemistry, electrophysiology and electron microscopy or underwent behavioral test. The functional effect of tau propagation was assessed by multielectrode array to evaluate light-evoked CA1 neuronal firing responses after optogenetic stimulation of Wfs1+ECII axons.
Results
Wfs1-Cre mice injected in ECII with AAV2/6-Flex-P301Ltau displayed significant human tau positivity in CA1 pyramidal neurons but not in DG at 4-weeks post-injection. Electron microscopy revealed a synaptic connection between ECII Wfs1+ axons and CA1 dendrites, and the presence of human tau in pre- and post-synaptic elements. Field recordings of CA1 pyramidal neurons showed reduced measures of excitability. Multielectrode array recordings of optogenetically stimulated Wfs1+ axons resulted in a reduced CA1 neuronal firing after AAV2/6-Flex-P301Ltau injection. Trace fear conditioning revealed deficits in trace and contextual memory in the AAV2/6-Flex-P301Ltau injected mice.
Conclusions
Expression of P301Ltau in Wfs1+ neurons in ECII spreads tau specifically to CA1 pyramidal neurons, and is accompanied by several measures of neurophysiological impairment, including reduced neuronal excitability and deficits in contextual memory.
PKR KINASE DIRECTLY REGULATES TAU EXPRESSION AND ALZHEIMER'S DISEASE-RELATED TAU PHOSPHORYLATION
Abstract
Aims
Deposition of extensively hyperphosphorylated tau in specific brain cells is a clear pathological hallmark in Alzheimer’s disease and other tauopathies. Furthermore, the well-established “tau hypothesis” postulate that hyperphosphorylation of tau abolishes its microtubule-stabilizing role, and leaves it vulnerable to self-assembly, thereby promoting neuronal dysfunction and death. This suggests a central role of hyperphosphorylation in tauopathies, but so far no disease-causing kinase has been identified. Here we investigate the relationship between acute encephalitis, activation of the inflammation/infection-activated kinase, PKR, and pathological tau phosphorylation.
Methods
PKRs role in tau phosphorylation was assessed via in vitro phosphorylation assays, cellular overexpression of constitutively active PKR, and PKR inhibition in rTg4510 mice brain slices, using specific phospho-tau antibodies. qPCR and microtubule-binding assays were also performed. Finally, to induce acute encephalopathy, robust inflammation, and PKR upregulation, Langat virus was intracranial injected in wild-type mice.
Results
We observe that PKR directly phosphorylates numerous abnormal and disease-modifying residues within tau including Thr181, Ser199/202, Thr231, Ser262, Ser396, Ser404 and Ser409. Similar, we find that these phosphorylations actively displace cellular tau from microtubules. In addition, PKR overexpression and knockdown, respectively, increase and decrease tau protein and mRNA levels in cells. Finally, acute encephalopathy induces robust inflammation and PKR upregulation, accompanied by abnormally phosphorylated full-length- and truncated tau.
Conclusions
These findings indicate that PKR, independent of other kinases, and upon acute brain inflammation, capably trigger pathological modulation of tau, which in turn, might form the initial pathologic seed in several tauopathies such as Alzheimer’s disease and Chronic traumatic encephalopathy where inflammation is severe.
THE ONSET OF HIPPOCAMPAL NETWORK CHANGES AND MEMORY DECLINE IS ASSOCIATED WITH AN IMMEDIATE EARLY GENE SIGNATURE IN P301S TAU TRANSGENIC MICE
Abstract
Aims
Tau hyperphosphorylation and deposition within the brain is a hallmark feature of several neurodegenerative diseases, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Furthermore, tau - but not Aβ pathology - correlates with neurodegeneration and cognitive decline in these diseases. However, how tau pathology drives cellular and molecular mechanisms in cognitive decline is not well understood.
Methods
Therefore, this study aims to investigate the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus utilizing the TAU58/2 tau transgenic mouse model. These mice express human P301S mutant tau and recapitulate essential features of AD and FTD, including tau pathology, early-onset disinhibition, and moderate motor deficits.
Results
Here, we found that the onset of spatial memory decline in TAU58/2 transgenic mice was accompanied by an impairment in long-term potentiation (LTP) and neuronal network aberrations during electrophysiological and electroencephalography (EEG) recordings. Further, gene-expression profiling at the onset of deficits in TAU58/2 mice revealed an immediate early gene (IEG) signature that is consistent with neuronal network hypersynchronicity. Finally, we determined that increased IEG activity was confined to neurons harbouring tau pathology, providing a cellular link between abnormal tau and neuronal network dysfunction.
Conclusions
Taken together, our data suggests that tau pathology drives neuronal network dysfunction by hyperexcitation of individual, pathology-harbouring neurons and is a major contributor to memory deficits. Furthermore, this study provides new insights into the pathomechanistic role of tau in disease and may thereby allow the identification of new targets for future translations into therapy.
TAU INDUCES ENDOTHELIAL SENESCENCE GENES AND HAS LASTING CONSEQUENCES FOR VASCULATURE
Abstract
Aims
Changes in cerebral vasculature integrity and function are common co-occurring events in Alzheimer’s disease (AD). We previously observed abnormal vasculature in an aged tauopathy mouse model. We hypothesized that if vascular abnormalities are the result of pathological tau species then reducing tau burden should reduce morphological and functional vascular changes.
Methods
We isolated microvessels from both human AD brain and aged rTg4510 tau over-expressing mice to determine if tau is associated with vasculature and to perform additional quantitative PCR analysis of gene changes. In mice, we made use of the doxycycline suppressible transgene cassette to determine if turning off tau expression could impact vascular dysfunction. In vivo two-photon microscopy was used to measure functional hyperemia in response to a visual stimulation task, vascular density, and capillary obstruction.
Results
Microvessel preparations were enriched for seed-competent bioactive tau and genes associated with cellular senescence. After visual stimulation, small arterioles in tau mice were observed to have a slower time to peak and reduced maximum dilation indicating impaired functional hyperemia. Turning off tau expression for 3 months reduced soluble tau burden to ~15% of the original levels but did not rapidly alter vascular density, capillary obstruction, or endothelial cell gene expression changes at this point in the disease course.
Conclusions
Tau expression has a substantial impact on endothelial health in microvessels in the brain, leading to senescence associated gene expression. These changes persist even after tau is largely removed, raising the possibility that this aspect of tau related pathological change may not respond to tau-directed therapies.
CONDENSED TAU CONFORMERS DISRUPT NUCLEAR TRANSPORT
Abstract
Aims
Germline mutations in the MAPT cause some forms of frontotemporal lobar degeneration (FTLD-MAPT). Mutant tau can promote alternative misfolding pathways engendering divergent tau conforms and representing clinical heterogeneity. The repertoire of tau conformers can include liquid-liquid phase separation (LLPS) under conditions of cell-free molecular crowding. In this study, pathobiology of tau conformers undergoing LLPS were studied in live reporter cells.
Methods
Seed-competent tau associated with a common behavioral variant of frontotemporal dementia were cloned by endpoint dilution; the cells were assayed for viability and biochemical markers of cell death and were also assessed by video microscopy and photobleaching to determine dynamic aspects of aggregate formation.
Results
Tau conformers present in FTLD-MAPT cases and transduced into reporter cells had a high propensity to condense on the nuclear envelope and disrupt nuclear-cytoplasmic transport. Nuclear envelope fluorescent tau signals and small fluorescent inclusions in a stable clonal line behaved as a demixed liquid state under live cell conditions; indicative of LLPS effects, these droplets exhibited spherical morphology, fusion events and recovery from photobleaching. While pathogenic mutations in some proteins can interfere with physiological functions of membrane-less organelles, a disease-causing MAPT mutation perturbed nuclear-cytoplasmic transport by gain-of-function formation of LLPS on the nuclear envelope, this acting as a molecular cue to trigger regulated cell death.
Conclusions
Our findings indicate that within a spectrum of alternative conformers, tau undergoing LLPS is a notably toxic species; demixed tau droplets recruiting on the nuclear envelope hinder nuclear-cytoplasmic transport.