Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer\'s disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.

Neurodegeneration is a progressive event leading to specific neuronal loss due to the accumulation of aberrant proteins. These pathologic forms of proteins further worsen and interfere with normal physiologic mechanisms, which can lead to abnormal proliferation of immune cells and subsequent inflammatory cascades and ultimately neuronal loss. Recently, immunotherapies targeting abnormal, pathologic forms of protein have shown a promising approach to modify the progression of neurodegeneration. Recent advances in immunotherapy have led to the development of novel antibodies against the proteinopathies which can eradicate aggregations of protein as evident from preclinical and clinical studies. Nonetheless, only a few of them have successfully received clinical approval, while others have been discontinued due to a lack of clinical efficacy endpoints. The current review discusses the status of investigational antibodies under clinical trials, their targets for therapeutic action, and evidence for failure or success.

OBJECTIVE: Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington\'s disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD.
METHODS: After characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand.
RESULTS: Plasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p < 0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R.
CONCLUSIONS: Overall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.

Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs. Recently, the Cingulin (CGN) protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss. Here, we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death. Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice, resembling the auditory phenotype in human patients. Interestingly, a human-specific residue (V1112) in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN. Moreover, the expression of heat shock factor 1 (HSF1) decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death. In summary, these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN, which can be targeted by the expression of the cell chaperone response regulator HSF1.

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.

Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimer\'s disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenic C. elegans model expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT in C. elegans causes neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with loss of pgrn-1, the C. elegans ortholog of human PGRN. Neither full nor partial loss of pgrn-1 altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout of spop-1, sut-2, and sut-6 resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.

Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of an uninterrupted polyglutamine (polyQ) repeat in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in fruit fly survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.

In patients with TDP43 proteinopathy, phosphorylated TDP43 (p-TDP43) accumulates in the cytoplasm of neurons. The accumulation of p-TDP43 has also been reported in patients with tauopathy and α-synucleinopathy. We investigated spatiotemporal changes in p-TDP43 accumulation in the brains of rTg4510 mice that overexpressed human mutant tau (P301L) and exhibited hyperphosphorylated tau (hp-tau) and phosphorylated αSyn (p-αSyn) accumulation. Immunohistochemically, p-TDP43 aggregates were observed in the cytoplasm of neurons, which increased with age. A significant positive correlation was observed between the number of cells with p-TDP43 aggregates and hp-tau and p-αSyn aggregates. Suppression of the human mutant tau (P301L) expression by doxycycline treatment reduces the accumulation of p-TDP43, hp-tau, and p-αSyn. Proteinase K-resistant p-TDP43 aggregates were found in regions with high hp-tau, and p-αSyn accumulation. Western blotting of the sarkosyl-insoluble fraction revealed bands of monomeric TDP43 and p-TDP43. These results indicate that the accumulation of mouse p-TDP43 is associated with the accumulation of human mutant tau (P301L) in rTg4510 mouse brains. The accumulation of hp-tau and p-αSyn may promote sarkosyl-insoluble p-TDP43 aggregates that are resistant to proteinase K. The synergistic effects of tau, TDP43, and αSyn may be involved in the pathology of proteinopathies, leading to the accumulation of multiple abnormal proteins.

The central nervous system (CNS) is widely recognized as the only organ system without lymphatic capillaries to promote the removal of interstitial metabolic by-products. Thus, the newly identified glymphatic system which provides a pseudolymphatic activity in the nervous system has been focus of latest research in neurosciences. Also, findings reported that, sleep stimulates the elimination actions of glymphatic system and is linked to normal brain homeostatis. The CNS is cleared of potentially hazardous compounds via the glymphatic system, particularly during sleep. Any age-related alterations in brain functioning and pathophysiology of various neurodegenerative illnesses indicates the disturbance of the brain\'s glymphatic system. In this context, β-amyloid as well as tau leaves the CNS through the glymphatic system, it\'s functioning and CSF discharge markedly altered in elderly brains as per many findings. Thus, glymphatic failure may have a potential mechanism which may be therapeutically targetable in several neurodegenerative and age-associated cognitive diseases. Therefore, there is an urge to focus for more research into the connection among glymphatic system and several potential brain related diseases. Here, in our current review paper, we reviewed current research on the glymphatic system\'s involvement in a number of prevalent neurodegenerative and neuropsychiatric diseases and, we also discussed several therapeutic approaches, diet and life style modifications which might be used to acquire a more thorough performance and purpose of the glymphatic system to decipher novel prospects for clinical applicability for the management of these diseases.

Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.