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Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies.The limited success of amyloid-β-targeting therapies for Alzheimer disease has led to a shift in focus towards the tau protein. This Review provides an update on the initial trials of tau-targeting therapies, focusing particularly on immunotherapies, and considers future directions for these therapies.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4 CRBN , and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

INTRODUCTION It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies. METHODS To address this, we performed in vivo two‐photon Ca2+ imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody. RESULTS Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function. DISCUSSION Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy. Highlights Neuronal hypofunction in awake and behaving mice in early stages of tauopathy. Altered network activity disrupted local circuitry engagement in tauopathy mice. Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice. Tau antibody acutely reduced soluble phospho‐tau and improved neuronal function.

Purpose: Studies suggest that deficits in auditory processing predict cognitive decline and dementia, but those studies included limited measures of auditory processing. The purpose of this study was to compare older adults with and without probable mild cognitive impairment (MCI) across two domains of auditory processing (auditory performance in competing acoustic signals and temporal aspects of audition). Method: The Montreal Cognitive Assessment (Nasreddine et al., 2005) was used to classify participants as with or without probable MCI. In this cross-sectional study, participants (n = 79) completed 4 measures of auditory processing: Synthetic Sentence Identification with Ipsilateral Competing Message (Gates, Beiser, Rees, D'Agostino, & Wolf, 2002), Dichotic Sentence Identification (Fifer, Jerger, Berlin, Tobey, & Campbell, 1983), Adaptive Tests of Temporal Resolution (ATTR; Lister & Roberts, 2006; across-channel and within-channel subtests), and time-compressed speech (Wilson, 1993; Wilson, Preece, Salamon, Sperry, & Bornstein, 1994). Audiometry was also conducted. Results: Those with probable MCI had significantly poorer performance than those without MCI on Synthetic Sentence Identification with Ipsilateral Competing Message, Dichotic Sentence Identification, and the ATTR within-channel subtest. No group differences were found for time-compressed speech, ATTR across-channel, or audiometric measures. Conclusions: Older adults with cognitive impairment not only have difficulty with competing acoustic signals but may also show poor temporal processing. The profile of auditory processing deficits among older adults with cognitive impairment may include multiple domains.

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance via the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In frontotemporal dementia (FTD) patient-derived neurons and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 significantly reduced tau levels and improved motor function in mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

Alzheimer’s disease (AD) is characterized by amyloid β plaques and neurofibrillary tau tangles (NFTs). While research has demonstrated amyloid pathology occurs prior to tau pathology, or tauopathy, tau has proven to be more toxic. Tauopathy is associated with cognitive declines and neurodegeneration. These findings have highlighted the importance of further understanding tauopathy. In the progression of tauopathy, there is an observable immune response that can be measured by glial cells such as microglia. Activated microglia are known to exacerbate tauopathy rather than reducing the pathology. Research has indicated that with increased age there is an increased risk for AD-related tauopathy and a more reactive, or primed immune response. Therefore, it is important to further understand how tauopathy and immune markers change in respect to age to potentially identify critical periods that might be advantageous for future interventions. This dissertation is aimed at understanding the effects of age and genetic mutant variants of tau in different animal models of tauopathy over three different studies. In study one, a commonly used transgenic model of tauopathy, rTg4510, was studied to examine how markers of tauopathy and tauopathy-related pathology differ over the life course. Regression analyses were conducted to determine the best models of fit (linear vs non-linear models of fit) for each marker. Results indicated that not all the markers of pathology in this model progress at the same rate or in the same manner. However, there was an overall increase in pathological events with increased age; especially in histological sections and the detergent insoluble homogenate fraction that contains pathological aggregates. In study two, age differences between young, middle-aged, and old animals that received either AAV9 GFP or AAV9 tau P301L intracranial injections were examined. Two-way ANOVAs and two-way repeated measures ANOVAs were conducted to determine group differences on measures of tauopathy, tauopathy-related markers of pathology including immune activation and neurodegeneration, and behavioral assessments of motor and cognitive impairments. These results indicated the old mice had higher levels of early phosphorylated tau, neurofibrillary tau tangles (NFTs), and reactive immune activation. Behavioral assessments evidenced a reduction in performance in the old animals irrespective of the injection group. However, only the younger GFP injected mice (young and middle-aged) were able to demonstrate mastery of the memory task. The old GFP and tauP301L injected mice were not able to achieve the historical learning criterion in the memory task. In study three, viral constructs expressing different tau variants were employed including, AAV9 tau P301L, AAV9 tau R406W, AAV9 tau wild-type, and AAV9 GFP intracranial injections were conducted in middle-aged mice to identify whether tau mutations associated with human disease could produce a translational model of tauopathy. One-way ANOVAs and one-way repeated measures ANOVAs were conducted for measures of tauopathy, tauopathy-related pathology including immune activation and neurodegeneration, and behavioral assessments to determine any motor or cognitive deficits. The results indicated that both tau P301L and tau wild-type created models of tauopathy that include declines in a behavioral memory task. However, these two viruses displayed different mechanisms that warrant further investigation. Tau P301L demonstrated the highest levels of insoluble tau and NFTs, similar to the rTg4510 model, while tau wild-type had the highest levels of histological phosphorylated tau, soluble tau, and exhibited the greatest amount of hippocampal atrophy. This body of work demonstrates the importance of age in both transgenic and viral models of tauopathy. As demonstrated by studies one and two, there are changes that occur in animal models that can demonstrate a progression of pathology. This progression is critical as translational models of AD-related tauopathy are imperative for furthering the knowledge of tau and potential treatments. Additionally, the viral models validate the need to understand earlier events in the progression of pathology. The tauP301L and tauwild-type viruses both modeled tauopathy. However, these viruses, did so in distinct ways that warrant further investigation to determine if there are differences early in the progression of pathology that are driving the observed differences found in age and/or viral differences.

We previously reported altered neuronal Ca dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca activity profile and decreasing pathological tau in these mice . Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models. In this study, we first performed in vivo two-photon Ca imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age. A more detailed populational analysis of the pattern of Ca activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region. Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies. Layer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy.Altered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running.Layer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions.Acute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction.