Rosemary J. Jackson

Tau association with synaptic vesicles causes presynaptic dysfunction

Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimers disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.

Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK

Human-to-human transmission of Creutzfeldt–Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aβ) protein associated with Alzheimer’s disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aβ seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aβ and give insights into the possibility of iatrogenic transmission of AD and CAA.

Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease

Alzheimers disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ‐plaques and synapse loss, with rTg21221 mice, which overexpress wild‐type human tau. When compared to the APP/PS1 mice without human tau, the cross‐sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque‐associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild‐type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque‐associated synapse loss.

Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse.

IntroductionNon-pathological, age-related cognitive decline varies markedly between individuals and places significant financial and emotional strain on people, their families and society as a whole. Understanding the differential age-related decline in brain function is critical not only for the development of therapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing such as Alzheimer’s disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people for whom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailed structural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, and epidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain; however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonal structure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy to allow the study of human synapses from the LBC1936 cohort in unprecedented morphological and molecular detail, using the high-resolution imaging techniques of array tomography and electron microscopy. This allows us to analyze the brain at sub-micron resolution to assess density, protein composition and health of synapses. Here we present data from the first donated LBC1936 brain and compare our findings to Alzheimer’s diseased tissue to highlight the differences between healthy and pathological brain ageing.ResultsOur data indicates that compared to an Alzheimer’s disease patient, the cognitively normal LBC1936 participant had a remarkable degree of preservation of synaptic structures. However, morphological and molecular markers of degeneration in areas of the brain associated with cognition (prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed.ConclusionsOur novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to now include neuro pathological changes, at the level of single synapses. This approach offers an unprecedented opportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in age-related cognitive change.

Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimers disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD. SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimers disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation.

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer\'s disease

Summary One of the key knowledge gaps blocking development of effective therapeutics for Alzheimer’s disease (AD) is the lack of understanding of how amyloid beta (Aβ) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau’s influence on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD. Highlights - Expression of human familial Alzheimer’s associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function. - Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression. - These data suggest that Aβ and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

Antidiabetic Polypill Improves Central Pathology and Cognitive Impairment in a Mixed Model of Alzheimer’s Disease and Type 2 Diabetes

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, being Alzheimer’s disease (AD) as the most common form. Both AD and T2D are closely related to aging and with a growing elderly population it might be of relevance to explore new therapeutic approaches that may slow or prevent central complications associated with metabolic disorders. Therefore, we propose the use of the antidiabetic polypill (PP), a pharmacological cocktail, commonly used by T2D patients that include metformin, aspirin, simvastatin, and an angiotensin-converting enzyme inhibitor. In order to test the effects of PP at the central level, we have long-term treated a new mixed model of AD-T2D, the APP/PS1xdb/db mouse. We have analyzed AD pathological features and the underlying specific characteristics that relate AD and T2D. As expected, metabolic alterations were ameliorated after PP treatment in diabetic mice, supporting a role for PP in maintaining pancreatic activity. At central level, PP reduced T2D-associated brain atrophy, showing both neuronal and synaptic preservation. Tau and amyloid pathologies were also reduced after PP treatment. Furthermore, we observed a reduction of spontaneous central bleeding and inflammation after PP treatment in diabetic mice. As consequence, learning and memory processes were improved after PP treatment in AD, T2D, and AD-T2D mice. Our data provide the basis to further analyze the role of PP, as an alternative or adjuvant, to slow down or delay the central complications associated with T2D and AD.

sAPPβ and sAPPα increase structural complexity and E/I input ratio in primary hippocampal neurons and alter Ca 2+ homeostasis and CREB1-signaling

ABSTRACT One major pathophysiological hallmark of Alzheimers disease (AD) is senile plaques composed of amyloid &bgr; (A&bgr;). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards A&bgr; production and soluble APP&bgr; (sAPP&bgr;) levels. A&bgr; is known to impair synaptic function; however, much less is known about the physiological functions of sAPP&bgr;. The neurotrophic properties of sAPP&agr;, derived from the non‐amyloidogenic pathway of APP cleavage, are well‐established, whereas only a few, conflicting studies on sAPP&bgr; exist. The intracellular pathways of sAPP&bgr; are largely unknown. Since sAPP&bgr; is generated alongside A&bgr; by &bgr;‐secretase (BACE1) cleavage, we tested the hypothesis that sAPP&bgr; effects differ from sAPP&agr; effects as a neurotrophic factor. We therefore performed a head‐to‐head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPP&agr; significantly increases axon length (p=0.0002) and that both sAPP&agr; and sAPP&bgr; increase neurite number (p<0.0001) of PHN at 7days in culture (DIV7) but not at DIV4. Moreover, both sAPP&agr;‐ and sAPP&bgr;‐treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (p<0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPP&agr; enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1‐signaling. Finally, we found that sAPP&agr; levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage‐dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond A&bgr; pathophysiology. HIGHLIGHTSsAPP&agr; and sAPP&bgr; have a critical stage‐dependent role in the developing glutamatergic system in vitro.sAPP&bgr; impacts in a different manner on the developing glutamatergic system compared to sAPP&agr;.Effects of sAPP&agr; are associated with CREB‐1 signaling.

Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development

Decreased expression but increased activity of PDK1 has been observed in neurodegenerative disease. To study in vivo function of PDK1 in neuron survival during cortical development, we generate forebrain-specific PDK1 conditional knockout (cKO) mice. We demonstrate that PDK1 cKO mice display striking neuron loss and increased apoptosis. We report that PDK1 cKO mice exhibit deficits on several behavioral tasks. Moreover, PDK1 cKO mice show decreased activities for Akt and mTOR. These results highlight an essential role of endogenous PDK1 in the maintenance of neuronal survival during cortical development.