Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

The “Shaken Baby” syndrome: pathology and mechanisms

The “Shaken Baby” syndrome (SBS) is the subject of intense controversy; the diagnosis has in the past depended on the triad of subdural haemorrhage (SDH), retinal haemorrhage and encephalopathy. While there is no doubt that infants do suffer abusive injury at the hands of their carers and that impact can cause catastrophic intracranial damage, research has repeatedly undermined the hypothesis that shaking per se can cause this triad. The term non-accidental head injury has therefore been widely adopted. This review will focus on the pathology and mechanisms of the three physiologically associated findings which constitute the “triad” and are seen in infants suffering from a wide range of non-traumatic as well as traumatic conditions. “Sub” dural bleeding in fact originates within the deep layers of the dura. The potential sources of SDH include: the bridging veins, small vessels within the dura itself, a granulating haemorrhagic membrane and ruptured intracranial aneurysm. Most neuropathologists do not routinely examine eyes, but the significance of this second arm of the triad in the diagnosis of Shaken Baby syndrome is such that it merits consideration in the context of this review. While retinal haemorrhage can be seen clinically, dural and subarachnoid optic nerve sheath haemorrhage is usually seen exclusively by the pathologist and only rarely described by the neuroradiologist. The term encephalopathy is used loosely in the context of SBS. It may encompass anything from vomiting, irritability, feeding difficulties or floppiness to seizures, apnoea and fulminant brain swelling. The spectrum of brain pathology associated with retinal and subdural bleeding from a variety of causes is described. The most important cerebral pathology is swelling and hypoxic–ischaemic injury. Mechanical shearing injury is rare and contusions, the hallmark of adult traumatic brain damage, are vanishingly rare in infants under 1 year of age. Clefts and haemorrhages in the immediate subcortical white matter have been assumed to be due to trauma but factors specific to this age group offer other explanations. Finally, examples of the most common causes of the triad encountered in clinical diagnostic and forensic practice are briefly annotated.     

Nervous system involvement in von Hippel–Lindau disease: pathology and mechanisms

Patients with von Hippel–Lindau disease carry a germline mutation of the Von Hippel–Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.     

Tau and α-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and alpha-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61-102, mean 84.1 +/- 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.     

Connatal (fetal) hydrocephalus: an acquired pathology?

We investigated the etiology of hydrocephalus present at birth, i.e. of fetal hydrocephalus. Both inherited and dysraphic major malformations are very rare. Intraventricular hemorrhages and viral infections during pregnancy are among the proposed etiologies; they are supported more by anatomical, physiopathological and experimental findings than by clinical evidence. Cases of fetal intraventricular hemorrhages cited in the literature are anecdotical, and the reports fail to identify maternal or fetal predisposing factors. The role of viruses in the etiology of connatal hydrocephalus has been postulated on the basis of epidemiological considerations in human pathology and of a considerable amount of experimental studies in animals. Investigations were generally focused on aqueduct ependyma, but research should also address other structures involved in the genesis of hydrocephalus (choroid plexus, extraventricular CSF pathways, including arachnoid villi). Furthermore, experimental evidence has emerged concerning a number of toxins and of drugs administered during pregnancy, which are thought to be involved in the genesis of hydrocephalus: once more, the conclusions reached in these experimental trials lend further credence to the human epidemiological data linking pregnancy disturbances with fetal hydrocephalus. Since most of these toxic agents are also thought to induce major malformations, we could assume the degree of their effect to depend on the embryonal stage affected: the earlier the action, the worse the malformation.Presented at the Consensus Conference: Hydrocephalus '92 Assisi, Italy, 26–30 April 1992     

The presence and origin of autoantibodies against α4 and α7 nicotinic acetylcholine receptors in the human blood: possible relevance to Alzheimer's pathology

Alzheimer's disease (AD) is characterized by a loss of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) in the brain and severe memory impairments. Previously, we found that antibodies elicited against extracellular domain of α7 nAChR subunit decreased the number of α7 nAChRs in the brains of mice and impaired episodic memory. Here we show that antibodies capable to bind α7(1-208) are present in the blood of both healthy humans and AD patients. In healthy individuals, their capacity to compete with [(125)-I]-α-bungarotoxin for the binding to α7(1-208) increased with age. The level of such antibodies was significantly elevated in children with severe form of obstructive bronchitis and in mice injected with Lewis lung carcinoma cells expressing both α4β2 and α7 nAChRs. Elevated antibody levels were accompanied with decreased surface nAChRs on the blood lymphocytes of children and of mice immunized with α7(1-208). Among AD patients, the level of α7 nAChR-specific antibodies was significantly larger in people 62.5 ± 1.5 years old with moderate or severe AD stages (15.2 ± 1.3 MMSE scores) compared to those of 76 ± 1.5 years old with the mild (22.7 ± 0.1 MMSE scores) AD stage. We concluded that α7(1-208) nAChR-specific antibodies found in the human blood are formed as a result of common infections accompanied with the destruction of respiratory epithelium. Elevated blood plasma levels of α7(1-208) nAChR-specific antibodies are characteristic for the early-onset AD and, therefore, are suggested as one of the risk factors for the development of this form of the disease.     

Co-Existence of tau and α-synuclein pathology in fetal graft tissue at autopsy: A case report

IntroductionTransplant of fetal ventral mesencephalic tissue into the striatum of Parkinson's disease (PD) patients has been performed to increase dopamine production and stimulate neuronal regeneration. Analysis of fetal graft tissue at autopsy has demonstrated 6 cases of α-synuclein pathology in PD patients, one case with both α-synuclein and tau pathology in a PD patient, and two cases of tau pathology within a Huntington's Disease patient.MethodsA 49 year old man with PD underwent bilateral fetal ventral mesencephalic cell transplants into the striatum. Autopsy at age 70 included immunohistochemical staining of host and graft tissue with antibodies to phosphorylated α-synuclein and phosphorylated tau protein.ResultsAutopsy confirmed the diagnosis of PD. Immunohistochemical staining of graft tissue demonstrated frequent neuronal perikaryal inclusions of phosphorylated α -synuclein and tau in the left graft only.ConclusionSpeculations on the formation of pathology include: 1) α-synuclein and tau pathology spread from host to the graft in a neuron-neuron manner. 2) The nature of the fetal cells themselves, or transplantation process, may render fetal tissue more susceptible to the spontaneous generation of pathology. 3) Factors within host environment caused native tau and α-synuclein in fetal tissue graft to become phosphorylated.     

Cerebral amyloid β(42) deposits and microvascular pathology in ageing baboons

M. Ndung'u, W. Härtig, F. Wegner, J. M. Mwenda, R. W. C. Low, R. O. Akinyemi and R. N. Kalaria (2012) Neuropathology and Applied Neurobiology 38, 487–499 Cerebral amyloid β(42) deposits and microvascular pathology in ageing baboons Background: Previous studies have extensively reported the deposition of amyloid β (Aβ) peptide with carboxyl‐ and amino‐terminal heterogeneity in cortical and cerebrovascular deposits in Alzheimer's disease (AD) and in non‐human primates except baboons. Methods: We examined the immunocytochemical distribution of Aβ peptides and Aβ oligomers in brain tissue from three subspecies of 18‐ to 28‐year‐old baboons (Papio) and in other monkeys including the squirrel (Saimiri sciureus) and rhesus (Macaca mulatta) for comparison. Results: A general preponderance of Aβ(42) in parenchymal deposits and many vascular deposits in all cortical lobes was evident in the baboons. Aβ oligomeric immunoreactivity was also apparent like to amyloid plaques. We found that the amino acid sequence of the Aβ domain of the baboon amyloid precursor protein is similar to that of man. In contrast to Aβ, immunoreactivity to hyperphosphorylated tau protein was largely intracellular and rare in these baboons. Brain tissues from squirrel and rhesus monkeys examined in parallel exhibited mostly vascular and parenchymal deposits containing Aβ(42) peptides. Our results were comparable to AD, but showed that even in younger monkeys exhibiting few deposits, Aβ(42) was evident in both parenchymal deposits and cerebral amyloid angiopathy. Perivascular amyloid deposits were frequent and often accompanied by microvascular abnormalities in the form of collapsed degenerated capillaries. Conclusions: Similar to other primates above and below in the phylogenetic order, our observations and evaluation of the literature implicate pathogenicity of Aβ(42) peptide associated with microvascular degeneration in baboons. We suggest baboons are useful animals to investigate the dynamics of AD‐related pathology.     

Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.     

Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.     

Arnold Netter (1855–1936) and infectious pathology of the nervous system

Arnold Netter (1855–1936) was a paediatrician who clinically applied the progress that his Pasteurian contemporaries had made possible through their bacteriological discoveries. From a neurological point of view, he brought looking for Kernig's sign into mainstream use to confirm the clinical diagnosis of meningitis and made diagnostic lumbar puncture systematic. He was one of the first to cure meningococcal and pneumococcal meningitis, long before the era of antibiotics, using subtractive lumbar puncture and intraspinal serotherapy. Netter's attentive vigilance enabled him to recognise, from its onset, the first poliomyelitis epidemic of the 20th century which took place in the summer of 1909. He described the clinical and epidemiological characteristics, identifying the viral rather than microbial origin.Netter detected the first cases of encephalitis lethargica in Paris in 1918. The disease had been described by Constantin von Economo (1876–1931) in Vienna the previous year. Netter spent fifteen years studying this new disease, which caused a pandemic a century ago. He filled in the clinical picture and used his understanding of cerebrospinal fluid and pathological anatomy to enhance knowledge and improve treatment of this neurological pathology.     

Hormesis and amyloid-β protein: physiology or pathology?

Hormesis is the concept that low doses of a toxin can have beneficial effects while high doses are harmful. This is also known as the inverted-U shaped dose-response curve. Hormesis appears to be a universal law for the function of memory mimetics. Amyloid-β protein is widely recognized to be a toxic agent responsible for plaque formation in Alzheimer's disease. In high doses it also produces amnesia. In lower, physiological doses, it enhances long term potentiation and memory. Blocking amyloid-β protein in animals without overproduction of the protein results in amnesia. At low doses, amyloid-β also increases neurite outgrowth, produces presynaptic enhancement, and may quench oxidative damage. It is postulated that both over- and underproduction of amyloid-β can lead to memory deficits. This is similar to a number of hormonal diseases, e.g., thyroid, where both low and high levels produce disease.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.     

Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)β(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)β(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)β(2)- and α(7)-selective agonists. Localization of α(4)β(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)β(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)β(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)β(2)- and α(7)-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)β(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)β(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)β(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)β(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.     

Peripheral inflammation and blood–brain barrier disruption: effects and mechanisms

The blood–brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.     

HDAC6 α-tubulin deacetylase: a potential therapeutic target in neurodegenerative diseases

Multiple sclerosis (MS) is a relatively common debilitating neurologic disease that affects people in early adulthood. While the characteristic pathology of MS has been well described, the etiology of the disease is not well understood, despite decades of research and the identification of strong genetic and environmental candidates for susceptibility. A question central to all diseases, but posed specifically for MS at the XVI European Charcot Foundation Lecture, was 'Can MS be prevented?' To address this question, we have evaluated the available data regarding nutritional and environmental factors that may be related to MS susceptibility and suggest the extent to which a potential intervention may reduce disease burden. It is our opinion that intervention, particularly supplementation with vitamin D, could have a dramatic impact on disease prevalence. Understanding that any intervention or behavioral modification will surely act in the context of genetic susceptibility and unidentified stochastic events, it is likely that not all MS is 'preventable'. Epidemiologic observation has provided key insights into environmental and nutritional factors that may alter one's susceptibility to MS, however, there are still many questions in unraveling the etiology of this complex disease.