Aims

ATTR amyloidosis is caused by the systemic deposition of amyloid fibrils of transthyretin that leads to organ failure and death. Like in other amyloid disorders, current treatments show limited effects in advanced cases. We hypothesized that the presence of preformed fibrils alters the fate of amyloid deposition, and this process represents a potential therapeutic strategy for advanced ATTR amyloidosis.

Methods

We extracted fibrils from ATTR amyloidosis patients to study the mechanism of amyloid deposition in the presence of preformed fibrils. We established a multidisciplinary program to develop peptide inhibitors, ranging from protein aggregation assays to x-ray crystallography structure determination and computational inhibitor design. We evaluated these peptide inhibitors in vitro, using patient samples, and in two Drosophila models. Finally, we engineered a biosensor cell line overexpressing a transthyretin variant that carries a disease-related mutation and a fluorescent tag for drug screening.

Results

In our studies, we discovered a novel mechanism of aggregation of transthyretin, common to other amyloid precursors. That is, we found that transthyretin can polymerize into amyloid fibrils by a templating mechanism known as amyloid seeding. Our results suggest that this mechanism takes over amyloid deposition at late stages of ATTR amyloidosis in contrast to de novo protein aggregation that triggers the disease. We found that current drugs that are effective in early states do not halt amyloid seeding of transthyretin. In contrast, our anti-seeding peptides show full inhibition of amyloid seeding at substoichiometric concentrations.

Conclusions

Anti-seeding peptides may represent a novel therapeutic avenue for advanced cases of ATTR amyloidosis.

Aims

Clearing amyloid-beta (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer’s disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in AD patients, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Therefore, the challenge of future AD treatments is to develop a therapeutic that robustly eliminates Aβ without inducing the pro-inflammatory side effects commonly associated with conventional antibodies.

Methods

In order to solve the dilemma of conventional antibody drugs, we develop a novel phagocytosis inducer for Aβ consisting of a single chain variable fragment (scFv) of an Aβ-targeting monoclonal antibody fused with a truncated receptor binding domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (Tyro3, Axl, and MerTK) receptors.

Results

This chimeric fusion protein (αAβ-Gas6) selectively eliminates Aβ plaques mainly through Axl receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, αAβ-Gas6 can induce synergistic clearance of Aβ by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination in AD model mice compared to Aβ antibody treatment.

Conclusions

Our results suggest that αAβ-Gas6 can be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.

Aims

Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that control gene expression. They may contribute to cognitive decline including Alzheimer’s disease (AD) and vascular dementia (VaD). Our objective was to assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized clinical trial of post-acute coronary syndrome patients with diabetes which lowered ischemic CVD events 18% (p=0.11).

Methods

MoCA (Montreal Cognitive Assessment) was performed on patients 70 years or older. In a prespecified analysis, participants were assigned to one of three groups: MoCA score ≥ 26 (normal performance), MoCA score 25 – 22 (mild cognitive impairment), and MoCA score ≤ 21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.

Results

464 participants were randomized to apabetalone or placebo in the cognition sub-study. Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of ≤ 21 (p=0.02) mostly contributed by the abstraction and recall domains, both of which saw greater improvements in the apabetalone treated participants compared to those on placebo (both p≤0.1). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% vs 7.9%).

Conclusions

Apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

Aims

Women are less vulnerable to neurodegenerative aspects of PD. We previously reported preserved alpha-synuclein (aSyn) homeostasis and reduced dopaminergic loss in female E46K-amplified (3K) aSyn transgenic mice, while estrogen treatment alleviated aSyn pathology and motor phenotypes in male 3K mice. Here, we study the underlying protective effects of estrogen receptor alpha (ERa) and impact of inhibiting the enzyme removing its membrane-stabilizing palmitoyl-tag in physiologically low 3K aSyn-expressing (3KL) mice.

Methods

Cognitive and motor performances were tested in various behavioral paradigms. We applied immunohistochemistry, (super-resolution) microscopy and immuno-EM to assess (sub)cellular localization and histopathology of aSyn and other proteins, quantitative WB/ELISA to study protein levels and biochemical distribution, and electrophysiology on hippocampal tissue slices to analyze synaptic plasticity. Estrogen receptor palmitoylation was measured using Acyl-Biotin Exchange assays.

Results

3KL female mice showed delayed onset of cognitive and motor symptoms, improved aSyn homeostasis (e.g. increased solubility/multimerization) and reduced Ser129-p aSyn cytopathology. Crowding of aSyn at vesicles was associated with impaired synaptic plasticity in 3KL males. Synaptic function was restored after estrogen treatment, which was blocked by ERa antagonists. In 3KL mice, ERa co-clustered at perinuclear and synaptic aSyn accumulations (as in the PD brain), which was associated with decreased ERa palmitoylation. We hence pharmacologically increased ERa palmitoylation using ML-348 (an APT-1 inhibitor) for 80 days, which improved synaptic plasticity and cognitive performances in 3KL (female and male) mice.

Conclusions

Increased synaptic ERa by female sex or ML-348-dependent palmitoylation preserves synaptic plasticity and aids phenotypes downstream the disturbed aSyn homeostasis in a 3KL aSyn PD mouse model.

Aims

Assess the feasibility and safety of concurrently delivering an investigational cell therapy, containing cell-growth and -survival factors, to the substantia nigra (SN) and nucleus basalis of Meynert (NBM) in patients with Parkinson’s disease (PD) at the time of deep brain stimulation (DBS) surgery.

Methods

Two participants with idiopathic PD demonstrating mild cognitive impairment underwent unilateral, stereotactic implantation of autologous regenerative peripheral nerve tissue (PNT) to the SN and NBM contralateral to the most affected side at the time they received bilateral DBS electrodes.

Results

Both participants (65M, 66F) successfully received unilateral PNT delivery to the SN and NBM areas. No serious adverse events related to the direct delivery of PNT were observed. However, one participant had worsening anxiety that prevented her from completing 12 month neurocognitive and PD severity scale assessments. Long-term follow up, 6 or 12 months post-implantation, showed stable performance on PD testing. Neurocognitive assessment for the one participant at 18 months post-surgery showed changes in phonemic fluency (z-score: -1.4), visuomotor construction and praxis (WAIS-IV Block Design: -1.0), mental flexibility and switching (TMT-B: -1.8), novel problem solving (WCST-64 Total Errors: +1.6), rote verbal learning (HVLT-R Total: +1.3), and delayed verbal recall (HVLT-R Delayed Recall: +1.5).

Conclusions

We report the successful direct delivery of an investigational cell therapy, as autologous PNT, to two separate targets at the time participants underwent DBS surgery. We plan to continue exploring the potential for this approach to modify the progression of damaged networks in neurodegenerative disorders.

Aims

The DIAN-TU Tau NexGen Platform trial will assess the safety, tolerability, biomarker, and cognitive efficacy of anti-tau therapies before and after tangle formation in dominantly inherited AD (DIAD) using a staggered, adaptive design with shared controls across treatment arms.

Tau species, including MTBR-tau which aggregate in tau tangles, increase in CSF and blood more than 10 years before tangles are detected by PET, and are closely associated with progression of Alzheimer pathology. This trial will investigate whether the monoclonal antibody, E2814, which targets soluble MTBR-tau, can limit disease progression in DIAD. To assure comparable background therapy, the anti-amyloid antibody lecanemab will be administered to participants.

The trial will enroll separate DIAD cohorts of pre-tangle, asymptomatic (CDR=0) and post-tangle, symptomatic (CDR=0.5-1.0) participants, randomizing each to E2814 or placebo. Lecanemab will be administered after E2814 in the asymptomatic cohort and before E2814 in the symptomatic cohort. Outcomes include clinical and cognitive measures, and biomarkers.

For the pre-tangle, asymptomatic cohort, CSF ptau217/tau217 at 4 years is the endpoint. For the post-tangle, symptomatic cohort, tau-PET at 2 and 4 years is primary endpoint. Target engagement will be assessed by CSF MTBR-tau and downstream effects on soluble t-tau, p-tau and MTBR tau; neurodegeneration by CSF and blood NfL and structural MRI; metabolism by FDG-PET; and amyloid-beta 42/40 by CSF and blood and amyloid-PET.

This is the first trial designed to assess if and when an anti-MTBR tau antibody, with background anti-amyloid antibody, will exert its targeted biomarker and clinical effects through disease progression in DIAD.