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One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse model (APP/PS1 + Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age‐related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1 + Tau model does not exhibit novel object memory or robust long‐term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aims: Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post‐mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10 + 16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule‐binding domains. Methods: We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex and RNA integrity matched participants who died without neurological disease (n = 12 FTDtau10 + 16 and 13 controls). Results: Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10 + 16 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10 + 16 cortex as well as a loss of presynaptic protein staining and region‐specific increased colocalization of phospho‐tau with synapses in temporal cortex. Conclusions: Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10 + 16 caused by the MAPT 10 + 16 mutation. [ABSTRACT FROM AUTHOR]

Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta (Aβ) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how Aβ leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds Aβ and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of Aβ binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n = 11) and control cases (n = 9). Within presynapses and post-synaptic densities, oligomeric Aβ generates a FRET signal with transmembrane protein 97. Further, Aβ generates a FRET signal with cellular prion protein, and post-synaptic density 95 within post synapses. Transmembrane protein 97 is also present in a higher proportion of post synapses in Alzheimer’s brain compared to controls. We inhibited Aβ/transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the allosteric modulator CT1812. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and Aβ. In human-induced pluripotent stem cell derived neurons, transmembrane protein 97 is present in synapses and colocalizes with Aβ when neurons are challenged with human Alzheimer’s brain homogenate. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of Aβ in human Alzheimer’s disease brain where it may mediate synaptotoxicity. [ABSTRACT FROM AUTHOR]

Background and purpose: Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well‐established excitatory synapse loss in AD with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses. Methods: Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals. Results: Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High‐resolution array tomography imaging revealed plaque‐associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques. Conclusions: Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy. [ABSTRACT FROM AUTHOR]

Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently observed that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), is associated with exacerbated synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. We examined brain tissue from 33 subjects (7–10 per group). We pooled tissue from all subjects in each group for unbiased proteomic analyses followed by validation with individual case samples. Our analysis identified over 5500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain and synapses are lost. Evidence from mouse models indicates that tau spreads trans -synaptically from pre- to postsynapses and that oligomeric tau is synaptotoxic, but data on synaptic tau in human brain are scarce. Here we used sub-diffraction-limit microscopy to study synaptic tau accumulation in postmortem temporal and occipital cortices of human Alzheimer's and control donors. Oligomeric tau is present in pre- and postsynaptic terminals, even in areas without abundant fibrillar tau deposition. Furthermore, there is a higher proportion of oligomeric tau compared with phosphorylated or misfolded tau found at synaptic terminals. These data suggest that accumulation of oligomeric tau in synapses is an early event in pathogenesis and that tau pathology may progress through the brain via trans -synaptic spread in human disease. Thus, specifically reducing oligomeric tau at synapses may be a promising therapeutic strategy for Alzheimer's disease. [Display omitted] • Oligomeric tau is present in synapses in Alzheimer's disease cortex • There is more oligomeric tau than phosphorylated or misfolded tau in synapses • Synaptic oligomeric tau is present even in areas without tangles • Oligomeric tau spreads from pre to post synapses in a mouse model Colom-Cadena and colleagues demonstrate using sub-diffraction-limit microscopy that synaptic oligomeric tau is a likely culprit in the spread of tau pathology through the brain in Alzheimer's disease. These data indicate that reducing oligomeric tau at synapses may be a promising therapeutic strategy to stop disease progression. [ABSTRACT FROM AUTHOR]

Summary: Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval. [Copyright &y& Elsevier]