Immunotherapeutic Approaches for the Treatment of Neurodegenerative Diseases: Challenges and Outcomes

Background: Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-β peptide, tau, α-synuclein, and mHTT, which cause Alzheimer’s disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson’s disease, Multiple system atrophy, Dementia with Lewy-body and Huntington’s disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases. Objectives: Literature survey of neurodegenerative diseases and immunotherapeutic approaches used to evaluate their pharmacological effects and future endeavours. Methods: A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com. Result: According to literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-β, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite of that, few of them produced desirable effects for the treatment of AD and PD. Conclusion: Several immunotherapeutic trials have shown promising outcomes against amyloid-β, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate promising role of immunotherapies against neurodegenerative diseases.

Therapeutic Application of rTMS in Atypical Parkinsonian Disorders

The terms atypical parkinsonian disorders (APDs) and Parkinson plus syndromes are mainly used to describe the four major entities of sporadic neuronal multisystem degeneration: progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and dementia with Lewy bodies (LBD). APDs are characterized by a variety of symptoms and a lack of disease modifying therapies; their treatment thus remains mainly symptomatic. Brain stimulation via repetitive transcranial magnetic stimulation (rTMS) is a safe and noninvasive intervention using a magnetic coil, and it is considered an alternative therapy in various neuropsychiatric pathologies. In this paper, we review the available studies that investigate the efficacy of rTMS in the treatment of these APDs and Parkinson plus syndromes. Τhe majority of the studies have shown beneficial effects on motor and nonmotor symptoms, but research is still at a preliminary phase, with large, double-blind studies lacking in the literature.

Neurofilament Levels Are Reflecting the Loss of Presynaptic Dopamine Receptors in Movement Disorders

Aims: Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker levels in the CSF are correlated to the loss of presynaptic dopamine transporters in neurons as detected with dopamine transporter SPECT (DaTscan).Methods: We retrospectively identified 47 patients (17 Alzheimer’s dementia, 10 idiopathic Parkinson’s disease, 7 Lewy body dementia, 13 progressive supranuclear palsy or corticobasal degeneration) who received a DaTscan and a lumbar puncture. DaTscan imaging was performed according to current guidelines, and z-scores indicating the decrease in uptake were software based calculated for the nucleus caudatus and putamen. The CSF biomarkers progranulin, total-tau, alpha-synuclein, NfL, and pNfH were correlated with the z-scores.Results: DaTscan results in AD patients did not correlate with any biomarker. Subsuming every movement disorder with nigrostriatal neurodegeneration resulted in a strong correlation between putamen/nucleus caudatus and NfL (nucleus caudatus right p < 0.01, putamen right p < 0.05, left p < 0.05) and between pNfH and putamen (right p < 0.05; left p < 0.042). Subdividing in disease cohorts did not reveal significant correlations. Progranulin, alpha-synuclein, and total-tau did not correlate with DaTscan results.Conclusion: We show a strong correlation of NfL and pNfH with pathological changes in presynaptic dopamine transporter density in the putamen concomitant to nigrostriatal degeneration. This correlation might explain the reported correlation of impaired motor functions in PD and NfL as seen before, despite the pathological heterogeneity of these diseases.

Cryo-EM structures of τ filaments from human brain

Electron cryo-microscopy (cryo-EM) has made it possible to determine near-atomic structures of τ filaments from human brain. Previous work had shown that the cores of paired helical and straight filaments of Alzheimer’s disease are made of two identical, but differently arranged C-shaped protofilaments. In recent years, cryo-EM has shown that the Alzheimer τ fold is 79 amino acids long. Five of the eight β-strands give rise to two antiparallel β-sheets, with the other three forming a β-helix. High-affinity binding sites of positron emission tomography ligand APN-1607 (PM-PBB3) are in the β-helix region. The Alzheimer fold contrasts with the 94 amino acid-long Pick fold, which is J-shaped and comprises nine β-strands that give rise to four antiparallel β-sheets, in the absence of a β-helix. Chronic traumatic encephalopathy τ fold is similar to the Alzheimer fold, but differs in the β-helix region, which is larger and contains a non-proteinaceous density that is probably hydrophobic. These folds are mostly two-layered. By contrast, the 107 amino acid τ fold of the 4R tauopathy corticobasal degeneration is four-layered and comprises 11 β-strands. It contains an internal, probably hydrophilic, density that is surrounded by τ. The τ folds described here share the presence of microtubule-binding repeats 3 and 4, as well as 10–13 amino acids after repeat 4.

Tau in Health and Neurodegenerative Diseases

Tau, one of the major microtubule-associated proteins, modulates the dynamic properties of microtubules in the mammalian nervous system. Tau is abundantly expressed in the brain, particularly in the hippocampus. Insoluble and filamentous inclusions of tau in neurons or glia are discovered in neurodegenerative diseases termed ‘tauopathies’, including Alzheimer’s disease (AD), argyrophilic grain disease (AGD), corticobasal degeneration (CBD), frontotemporal dementia (FTD), Pick’s disease (PiD) and progressive supranuclear palsy (PSP). Accumulation of intracellular neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau, is directly correlated with the degree of Alzheimer\'s dementia. This chapter reviews the role of tau protein in physiological conditions and the pathological changes of tau related to neurodegenerative diseases. The applications of tau as a therapeutic target are also discussed.

Case Report: Concomitant Alzheimer's and Lewy-Related Pathology Extending the Spectrum of Underlying Pathologies of Corticobasal Syndrome

Corticobasal syndrome (CBS) is clinically characterized by progressive asymmetric rigidity and apraxia together with symptoms suggestive of cortical involvement and basal ganglia dysfunction. The spectrum of neurodegenerative diseases that can manifest with CBS is wide. The associations of CBS with corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, frontotemporal lobar degenerations, Creutzfeldt–Jakob disease, or diffuse Lewy body pathology have been reported. We describe the case of a 71-year-old woman with CBS. The histopathological examination of brain tissue revealed concomitant pathology corresponding to the limbic stage of Lewy-related pathology and the intermediate stage of Alzheimer's-type pathology. To date, there have been only a few cases with a similar combination of pathology manifesting with the CBS phenotype that have been described in the literature. The extent and distribution of pathological changes in these cases were somewhat different from ours, and significance for clinical manifestation was attributed to only one of these pathologies. In our case, we assume that both types of pathology contributed to the development of the disease, considering the presumed specific spread of both types of pathological processes according to Braak's staging. Our case expands the spectrum of neurodegenerative pathological processes that may manifest with the typical CBS phenotype. Also, it points out the importance of identifying specific biomarkers that would enable more accurate in vivo differential diagnosis and more accurate determination of the underlying pathological processes of these diseases.