Isabel Costantino

Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue

To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F‐18]‐AV‐1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.

Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain

Tau pathology is known to spread in a hierarchical pattern in Alzheimers disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.

Pathological correlations of [F‐18]‐AV‐1451 imaging in non‐alzheimer tauopathies

Recent studies have shown that positron emission tomography (PET) tracer AV‐1451 exhibits high binding affinity for paired helical filament (PHF)‐tau pathology in Alzheimers brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV‐1451 binding patterns in three autopsy‐confirmed non‐Alzheimer tauopathy cases.

Validating novel tau PET tracer [F-18]-AV-1451 (T807) on postmortem brain tissue

To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F‐18]‐AV‐1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.

Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients

Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimers disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high‐molecular‐weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.

Seed‐competent HMW tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients

Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimers disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high‐molecular‐weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.

Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

Aggregation of Aβ amyloid fibrils into plaques in the brain is a universal hallmark of Alzheimer’s Disease (AD), but whether plaques in different individuals are equivalent is unknown. One possibility is that amyloid fibrils exhibit different structures and different structures may contribute differentially to disease, either within an individual brain or between individuals. However, the occurrence and distribution of structural polymorphisms of amyloid in human brain is poorly documented. Here we use X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid. Our observations indicate that (i) tissue derived from subjects with different clinical histories may contain different ensembles of fibrillar structures; (ii) plaques harboring distinct amyloid structures can coexist within a single tissue section and (iii) within individual plaques there is a gradient of fibrillar structure from core to margins. These observations have immediate implications for existing theories on the inception and progression of AD.

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.

Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.

Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue: Validation of PET Tracer

To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F‐18]‐AV‐1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.

A unique high-molecular-weight tau species is involved in propagation and accumulates in the cerebrospinal fluid of Alzheimer’s disease patients

P3-071 A UNIQUE HIGH-MOLECULAR-WEIGHT TAU SPECIES IS INVOLVED IN PROPAGATION AND ACCUMULATES IN THE CEREBROSPINAL FLUID OFALZHEIMER’S DISEASE PATIENTS Shuko Takeda, Caitlin Commins, Susanne Wegmann, Allyson D. Roe, Zhanyun Fan, Sarah L. DeVos, Isabel Costantino, Ana Trisini Lipsanopoulos, Matthew P. Frosch, Bradley T. Hyman, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Harvard NeuroDiscovery Center Biomarker Study, Boston, MA, USA. Contact e-mail: STAKEDA@mgh.harvard.edu