The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.

To investigate the natural history and outcomes following treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).

Macrophages are abundant in the cochlea; however, their role in hearing loss is not well understood. Insults to the cochlea, such as noise or insertion of a cochlear implant, cause an inflammatory response, which includes activation of tissue-resident macrophages. Activation is characterized by changes in macrophage morphology, mediator expression, and distribution. Evidence from other organs shows activated macrophages can become primed, whereby subsequent insults cause an elevated inflammatory response. Primed macrophages in brain pathologies respond to circulating inflammatory mediators by disproportionate synthesis of inflammatory mediators. This signaling occurs behind an intact blood-brain barrier, similar to the blood-labyrinth barrier in the cochlea. Local tissue damage can occur as the result of mediator release by activated macrophages. Damage is typically localized; however, if it is to structures with limited ability to repair, such as neurons or hair cells within the cochlea, it is feasible that this contributes to the progressive loss of function seen in hearing loss. We propose that macrophages in the cochlea link risk factors and hearing loss. Injury to the cochlea causes local macrophage activation that typically resolves. However, in susceptible individuals, some macrophages enter a primed state. Once primed, these macrophages can be further activated, as a consequence of circulating inflammatory molecules associated with common co-morbidities. Hypothetically, this would lead to further cochlear damage and loss of hearing. We review the evidence for the role of tissue-resident macrophages in the cochlea and propose that cochlear macrophages contribute to the trajectory of hearing loss and warrant further study.

Superresolution (SR) optical microscopy has allowed the investigation of many biological structures below the diffraction limit; however, most of the techniques are hampered by the need for fluorescent labels. Nonlinear label-free techniques such as second-harmonic generation (SHG) provide structurally specific contrast without the addition of exogenous labels, allowing observation of unperturbed biological systems. We use the photonic nanojet (PNJ) phenomena to achieve SR-SHG. A resolution of with respect to the fundamental wavelength, that is, a -fold improvement over conventional or diffraction-limited SHG under the same imaging conditions is achieved. Crucially we find that the polarization properties of excitation are maintained in a PNJ. This is observed in experiment and simulations. This may have widespread implications to increase sensitivity by detection of polarization-resolved SHG by observing anisotropy in signals. These new, to the best of our knowledge, findings allowed us to visualize biological SHG-active structures such as collagen at an unprecedented and previously unresolvable spatial scale. Moreover, we demonstrate that the use of an array of self-assembled high-index spheres overcomes the issue of a limited field of view for such a method, allowing PNJ-assisted SR-SHG to be used over a large area. Dysregulation of collagen at the nanoscale occurs in many diseases and is an underlying cause in diseases such as lung fibrosis. Here we demonstrate that pSR-SHG allows unprecedented observation of changes at the nanoscale that are invisible by conventional diffraction-limited SHG imaging. The ability to nondestructively image SHG-active biological structures without labels at the nanoscale with a relatively simple optical method heralds the promise of a new tool to understand biological phenomena and drive drug discovery.

Various lines of evidence implicate oxidative stress in the pathogenic mechanism(s) underpinning tauopathies. Consequently, antioxidant therapies have been considered in clinical practice for the treatment of tauopathies such as Alzheimer's disease (AD), but with mixed results. We and others have previously reported increased protein oxidation upon expression of both human 0N3R (hTau ) and 0N4R (hTau ) tau in vivo. Building on these studies, we demonstrate here the suppression of hTau associated phenotypes in Drosophila melanogaster after treatment with vitamin C or vitamin E. Curiously the rescue of phenotype was seen without alteration in total tau level or alteration in phosphorylation at a number of disease-associated sites. Moreover, treatment with paraquat, a pro-oxidant drug, did not exacerbate the hTau phenotypes. This result following paraquat treatment is reminiscent of our previous findings with hTau which also causes greater oxidative stress when compared to hTau but has a milder phenotype. Collectively our data imply that the role of oxidative stress in tau-mediated toxicity is not straight forward and there may be isoform-specific effects as well as contribution of other factors. This may explain the ambiguous effects of anti-oxidant treatments on clinical outcome in dementia patients.

To determine if Electrode Voltage (EV) measurements are potentially suitable as a test for detecting extra-cochlear electrodes in cochlear implants (CIs).

The reasons for soft failure after cochlear implantation require investigation. This study proposes a method to study and characterize the tissue response to the array in a case of soft failure in a person undergoing reimplantation.

Microplastic pollution is an urgent global issue. While spectroscopic techniques have been widely used for the identification of plastics collected from aquatic environments, these techniques are often labor-intensive and time-consuming due to sample collection, preparation, and long measurement times. In this study, a method for the two-dimensional detection and classification of flowing microplastic and organic biotic particles with high spatial and temporal resolutions has been proposed based on the simultaneous detection of coherent anti-Stokes Raman scattering (CARS) and two-photon excited autofluorescence (TPEAF) signals. Poly(methyl methacrylate) (PMMA), polystyrene (PS), and low-density polyethylene (LDPE) particles with sizes ranging from several tens to hundreds of micrometers were selectively detected in flow with an average velocity of 4.17 mm/s by CARS line scanning. With the same flow velocity, flowing PMMA and alga particles were measured using a multimodal system of CARS and TPEAF signals. The average intensities of both PMMA and alga particles in the CARS signals at a frequency of 2940 cm were higher than the background level, while only algae emitted TPEAF signals. This allowed the classification of PMMA and alga particles to be successfully performed in flow by the simultaneous detection of CARS and TPEAF signals. With the proposed method, the monitoring of microplastics in a continuous water flow without collection or extraction is possible, which is game-changing for the current sampling-based microplastic analysis.

Alzheimer's disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss, typically affecting individuals from mid-life onwards. Its multifactorial aetiology and the lack of any effective treatments has spurred the development of animal models as research and drug discovery tools. Several rodent models have been developed which recapitulate key features of AMD and provide insights into its underlying pathology. These have contributed to making significant progress in understanding the disease and the identification of novel therapeutic targets. However, a major caveat with existing models is that they do not demonstrate the full disease spectrum. In this review, we outline advances in rodent AMD models from the last decade. These models feature various hallmarks associated with AMD, including oxidative stress, hypoxia, immune dysregulation, genetic mutations and environmental risk factors. The review summarises the methods by which each model was created, its pathological characteristics as well as its relation to the disease in humans.

Collagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF) in bone forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we have used a murine osteocalcin-specific knockout (OcnVEGFKO) and performed multiscale analysis at the tibiofibular junction of both sexes. Furthermore, we also deleted in OBs extracted from male and female mice in an attempt to link sex-specific matrix signatures to deviations in gene expression. Label-free and non-destructive polarisation-resolved second harmonic generation microscopy (p-SHG) revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied only in males by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-stand stability, in addition to matrix carbonation and mineralisation. V deletion in male and female murine OB cultures further highlighted divergence in genes regulating local ECM structure including , , and The current results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders which clinically manifest in both pathological nano and macro-level disorganisation.

We demonstrate a continuous wave (CW) seeded synchronization-free optical parametric amplifier (OPA) pumped by a picosecond, 1 µm laser and show its performance when used as a simple yet powerful source for label-free coherent anti-Stokes Raman scattering (CARS), concurrent second harmonic generation (SHG), and two-photon fluorescence microscopy in an epi-detection geometry. The average power level of above 175 mW, spectral resolution of 8 cm, and 2 ps pulse duration are well optimized for CARS microscopy in bio-science and bio-medical imaging systems. Our OPA is a much simpler setup than either the "gold-standard" laser and optical parametric oscillator (OPO) combination traditionally used for CARS imaging, or the more recently developed OPA systems pumped with femtosecond pulses [1]. Rapid and accurate tuning between resonances was achieved by changing the poled channels and temperature of the periodically-poled lithium niobate (PPLN) OPA crystal together with the OPA seed wavelength. The Pump-Stokes frequency detuning range fully covered the C-H stretching band used for the imaging of lipids. By enabling three multiphoton techniques using a compact, synchronization free laser source, our work paves the way for the translation of label-free multi-photon microscopy imaging from biomedical research to an imaging based diagnostic tool for use in the healthcare arena.

Inflammation plays a key role in the aetiology and progression of Alzheimer's disease (AD). However, the immunophenotype of the second most common neurodegenerative cause of dementia, dementia with Lewy bodies (DLB), remains unclear. To date there have been no studies examining peripheral inflammation in DLB using multiplex immunoassay and flow cytometry concomitantly. We hypothesised that, using blood biomarkers, DLB would show an increased proinflammatory profile compared with controls, and that there would be a distinct profile compared with AD.

Age-related hearing loss (ARHL) has recently been confirmed as a common complex trait, that is, it is heritable with many genetic variants each contributing a small amount of risk, as well as environmental determinants. Historically, attempts to identify the genetic variants underlying the ARHL have been of limited success, relying on the selection of candidate genes based on the limited knowledge of the pathophysiology of the condition, and linkage studies in samples comprising related individuals. More recently genome-wide association studies have been performed, but these require very large samples having consistent and reliable phenotyping for hearing loss (HL), and early attempts suffered from lack of reliable replication of their findings. Replicated variants shown associated with ARHL include those lying in genes GRM7, ISG20, TRIOBP, ILDR1, and EYA4. The availability of large biobanks and the development of collaborative consortia have led to a breakthrough over the last couple of years, and many new genetic variants associated with ARHL are becoming available, through the analysis publicly available bioresources and electronic health records. These findings along with immunohistochemistry and mouse models of HL look set to help disentangle the genetic architecture of ARHL, and highlight the need for standardization of phenotyping methods to facilitate data sharing and collaboration across research networks.

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.

Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APP/PS1 mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APP/PS1 brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to Aβ in APP/PS1 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tau-toxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.

Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a characteristic deposition of IsoD-Aβ in blood vessel walls and pE3-Aβ within neurons. Both AD and OC showed positive associations between IsoD-Aβ and Aβ (p = 0.003 in AD and p = 0.001 in OC) and between IsoD-Aβ and pE3-Aβ (p = 0.001 in AD and OC). This last association was the only significant pE3-Aβ correlation identified in AD, whereas in the control cohorts pE3-Aβ also correlated with Aβ and AβPP (p = 0.001 in OC and p = 0.010 in YC).Our analyses suggest that IsoD-Aβ accumulation starts with ageing; whereas pE3-Aβ deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aβ in AD pathogenesis.

Alzheimer's disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood.

Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer's disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3β, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic models and cultured neuroblastoma cells.

Tauopathies are a group of disorders in which the deposition of abnormally folded tau protein accompanies neurodegeneration. The development of methods for detection and classification of pathological changes in protein conformation are desirable for understanding the factors that influence the structural polymorphism of aggregates in tauopathies. We have previously demonstrated the utility of Raman spectroscopy for the characterization and discrimination of different protein aggregates, including tau, based on their unique conformational signatures. Building on this, in the present study, we assess the utility of Raman spectroscopy for characterizing and distinguishing different conformers of the same protein which in the case of tau are unique tau strains generated . We now investigate the impact of aggregation environment, cofactors, post-translational modification and primary sequence on the Raman fingerprint of tau fibrils. Using quantitative conformational fingerprinting and multivariate statistical analysis, we found that the aggregation of tau in different buffer conditions resulted in the formation of distinct fibril strains. Unique spectral markers were identified for tau fibrils generated using heparin or RNA cofactors, as well as for phosphorylated tau. We also determined that the primary sequence of the tau monomer influenced the conformational signature of the resulting tau fibril, including 2N4R, 0N3R, K18 and P301S tau variants. These results highlight the conformational polymorphism of tau fibrils, which is reflected in the wide range of associated neurological disorders. Furthermore, the analyses presented in this study provide a benchmark for the Raman spectroscopic characterization of tau strains, which may shed light on how the aggregation environment, cofactors and post-translational modifications influence tau conformation in future studies.

The cerebral vasculature is made up of highly specialized structures that assure constant brain perfusion necessary to meet the very high demand for oxygen and glucose by neurons and glial cells. A dense, redundant network of arteries is spread over the entire pial surface from which penetrating arteries dive into the cortex to reach the neurovascular units. Besides providing blood to the brain parenchyma, cerebral arteries are key in the drainage of interstitial fluid (ISF) and solutes such as amyloid-beta. This occurs along the basement membranes surrounding vascular smooth muscle cells, toward leptomeningeal arteries and deep cervical lymph nodes. The dense microvasculature is made up of fine capillaries. Capillary walls contain pericytes that have contractile properties and are lined by a highly specialized blood-brain barrier that regulates the entry of solutes and ions and maintains the integrity of the composition of ISF. They are also important for the production of ISF. Capillaries drain into venules that course centrifugally toward the cortex to reach cortical veins and empty into dural venous sinuses. The walls of the venous sinuses are also home to meningeal lymphatic vessels that support the drainage of cerebrospinal fluid, although such pathways are still poorly understood. Damage to macro- and microvasculature will compromise cerebral perfusion, hamper the highly synchronized movement of neurofluids, and affect the drainage of waste products leading to neuronal and glial degeneration. This review will present vascular anatomy, their role in fluid dynamics, and a summary of how their dysfunction can lead to neurodegeneration.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in the walls of cerebral vessels, leading to complications such as intracerebral hemorrhage, convexity subarachnoid hemorrhage and cerebral microinfarcts. Patients with CAA-related intracerebral hemorrhage are more likely to develop dementia and strokes. Several pathological investigations have demonstrated that more than 90% of Alzheimer's disease patients have concomitant CAA, suggesting common pathogenic mechanisms. Potential causes of CAA include impaired Aβ clearance from the brain through the intramural periarterial drainage (IPAD) system. Conversely, CAA causes restriction of IPAD, limiting clearance. Early intervention in CAA could thus prevent Alzheimer's disease progression. Growing evidence has suggested Taxifolin (dihydroquercetin) could be used as an effective therapy for CAA. Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects, and provide protection against advanced glycation end products and mitochondrial damage. It has also been shown to facilitate disassembly, prevent oligomer formation and increase clearance of Aβ in a mouse model of CAA. Disturbed cerebrovascular reactivity and spatial reference memory impairment in CAA are completely prevented by Taxifolin treatment. These results highlight the need for clinical trials on the efficacy and safety of Taxifolin in patients with CAA.

Alzheimer's disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are two key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aβ led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aβ and tested in Alzheimer's disease, the field has progressed to targeting other proteins including αSyn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however, cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. Here we provide a background understanding to the key concepts and challenges involved in therapeutic design. This review further provides a comprehensive comparison between experimental and clinical studies in Aβ and αSyn immunotherapy and aims to determine the possible reasons for the disconnection in their outcomes.

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.