Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin

Amyloid β-peptide-induced progressive neurodegeneration in an APP-transgenic mouse model for Alzheimer’s disease

The amyloid beta-protein (Abeta) is the main component of Alzheimer's disease (AD)-related senile plaques. In the human brain Abeta-deposition occurs in a hierarchical sequence in which different areas of the brain become involved. It is not clear whether this sequence shows the time course of Abeta-deposition or just different pathology in different individuals. Although Abeta is associated with the development of AD it has not been shown which forms of Abeta induce neurodegeneration in vivo, which types of neurons are vulnerable and whether Abeta-induced neurodegeneration increases with the progression of Abeta-pathology. To address these questions, DiI-crystals were implanted into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP and of wild-type littermates. In parallel, immunohistochemistry for Abeta-plaque detection was performed in 3-, 5-, 11-, 15- and 25-month-old APP23 mice and wild-type littermates. Traced commissural neurons in layer III of the right frontocentral cortex were quantified in 3-, 5-, 11-, and 15-month-old mice. Three different types of commissural neurons were traced. At 3 months of age no differences in the number of labeled commissural neurons were seen in APP23 mice compared to wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared to wild-type animals at 5, 11, and 15 months of age, starting with the deposition of Abeta-plaques occurred in the frontocentral cortex at 5 months of age. The other two types of commissural neurons did not show alterations in 5- and 11-month animals. At 15 months of age, the number of traced sparsely ramified pyramidal neurons was reduced in addition to that of the heavily ramified neurons in APP23 mice compared with wild-type mice. At this point in time Abeta-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. At 25 months of age Abeta-deposits were also seen at the brainstem. In summary, the results show that 1) Abeta-deposition in APP23 mice follows a similar sequence as in human brain, in which the different areas become step-by-step involved in beta-amyloidosis, 2) this step-by-step regional involvement represents the time course of Abeta-deposition in the brain, and 3) Abeta thereby, induces progressive degeneration of distinct types of commissural neurons. Degeneration of the most vulnerable neurons starts in parallel with the occurrence of the first fibrillar Abeta deposits in the neocortex. The selective vulnerability of different types of neurons to Abeta is presumably related to the complexity of their dendritic morphology. In so doing, these results support Abeta to be the major therapeutic target for AD treatment in pre-clinical as well as in late stages of the disease

An investigation of a vitamin D, ionised calcium and parathyroid hormone regulatory axis of cerebral capillary function: Implications for cognitive performance in ageing

Increasing evidence suggests compromised integrity of cerebral capillary endothelium precedes cognitive impairment and the onset of Alzheimer’s disease and vascular dementia. Results from in vivo animal model studies demonstrated novel findings of potential detrimental effects of hypervitaminosis D on cerebral capillary integrity. Verbal episodic memory performance was negatively associated with vitamin D homeostasis in healthy older-aged adults. Overall, the use of vitamin D (VD) supplements should be considered only in context of VD deficiency

Tortuosity and other vessel attributes for arterioles and venules of the human cerebral cortex

Despite its demonstrated potential in the diagnosis and/or staging of disease, especially in oncology, tortuosity has not received a formal and unambiguous clinical definition yet. Using idealized three-dimensional vessel models (wavy helices) with known characteristics, we first demonstrate that, among various possible tortuosity indices, the standard deviation of the curvature Ksd best satisfies i) scale invariance and ii) positive monotonic response with respect to the amplitude and frequency of vessel oscillations. Ksd can thus be considered as a robust measure of tortuosity. On the contrary, indices previously considered as tortuosity metrics, such as the distance factor metrics (DFM), are highly scale dependent and inappropriate for that purpose. The tortuosity and other vessel attributes (curvature, length-to-diameter ratio (LDR),…) of more than 15,000 cortical vessels are subsequently studied, establishing their statistical properties as a function of the vessel nature (arterioles versus venules) or topological order (hierarchical position). In particular, arterioles have a higher LDR than venules, but the two kinds of vessels have the same mean curvature and tortuosity.Moreover, the lower the order of the vessels, i.e. the nearer to the capillary network, the more curved and tortuous they are. These results provide an essential reference both for diagnosis and for a future large reconstruction of the cerebral microvascular network

Imaging Alzheimer’s Disease Beta-amyloid Pathology in Transgenic Mouse Models Using Positron Emission Tomography

Accumulation of beta-amyloid (Aβ) in the brain is known to have an important role in the complex chain of pathological events leading to Alzheimer’s disease (AD). Based on current knowledge, Aβ is also seen as an interesting target for novel disease modifying therapies. Non-invasive and quantitative imaging of transgenic mouse models of AD by positron emission tomography (PET) would represent an ideal translational approach for evaluation of novel Aβ targeted therapeutics in vivo already during the preclinical phase of drug development. The aim of this thesis was to evaluate the suitability of Aβ targeted PET tracers, 11C-PIB and 18F-flutemetamol, for small animal PET imaging and for longitudinal follow-up of β-amyloidosis in three AD mouse models, i.e. transgenic APP23, Tg2576 and APPswe-PS1dE9 mice. In addition, the effect of novel functionalized Aβ targeted nanoliposomes, known as mApoE-PA-LIPs, were investigated in APP23 mice exploiting longitudinal 11C-PIB PET imaging. A temporal increase in tracer retention reflecting increased Aβ-deposition could be detected in vivo only in the APP23 mouse model. Both tracers specifically bound Aβ in mouse brain sections, however, the higher non-specific binding of [18F]flutemetamol to the white matter structures limited its sensitivity in comparison to 11C-PIB. In the APP23 model, the mApoE-PA-LIP treatment showed a trend to reduce the increase in the 11C-PIB binding ratios as compared to the saline-treated group; in addition, the binding ratios correlated well with the histologically-assessed amyloid load, further validating the method. In summary, these results demonstrate that 11C-PIB binding is a valid biomarker of Aβ deposition in the APP23 mouse – an animal model that expresses abundant, large and congophilic Aβ deposits. However, the sensitivity of the method is not sufficient for use in animal models with lower plaque loads and different plaque morphologies, nor does it seem capable of detecting early pathological changes in young AD mice.Siirretty Doriast

Activity- and pharmacology-dependent modulation of adult neurogenesis in relation to Alzheimer’s disease

In de hersenen van een volwassen mens zijn stamcellen aanwezig. Deze delen zich om nieuwe neuronen te produceren. Dit proces heet neurogenese, en speelt een belangrijke rol bij verschillende hersenprocessen. De vraag is echter of stamcellen therapeutisch kunnen worden ingezet voor de behandeling van bijvoorbeeld de ziekte van Alzheimer, een ziekte waarbij neuronen vroegtijdig afsterven. Michael Marlatt laat zien dat lichaamsbeweging bij muizen ervoor zorgt dat neurogenese in de hersenen toeneemt. Daarnaast voorkomt lichaamsbeweging een leeftijd-gerelateerde afname van ruimtelijk geheugen. Ook bevestigt de aanwezigheid van neurogenese in de amygdala, een hersengebied dat een belangrijke rol speelt bij emoties. Zijn bevindingen zijn bemoedigend voor de toekomstige behandeling van de ziekte van Alzheimer. Mogelijk kan lichaamsbeweging of medicijnen de geheugenproblemen die met de ziekte geassocieerd worden, terugdraaien

Cerebral and CSF amyloid load, and recovery of semantic material in Alzheimer disease patients

According to the new diagnostic criteria, the term “Alzheimer Disease” (AD) refers to a set of neuropathological changes that can be evaluated in vivo, rather than to a specific clinical symptomatology1. It is now widely accepted that β-Amyloid (Aβ42) in the cerebrospinal fluid is a valid indicator of alteration of the pathophysiological state, associated with fibrillar deposits of cerebral β-amyloid2. Comparative studies between imaging and autopsy findings have established that amyloid PET images are a valid in vivo surrogate for deposition of fibrillar β-amyloid3-10. We analyzed the values of cerebral spinal cord (CSF) biomarkers in 40 patients with clinical diagnosis of AD. Two groups emerged: the first with both clinical and liquor biomarkers consistent with AD; the second was clinically in line with AD, but it was missing its pathognomic CSF biomarkers. At this point we asked ourselves about the nosological entity of the second group. All patients underwent flutemetamol-PET and the second group was dichotomically divided into two more groups based on the PET report. Schematically: Group 1: CSF + / PET +; Group 2: CSF- / PET +; Group 3: CSF- / PET-. Our study then correlated the PET images through statistical software (spm12) in order to highlight any differences in cerebral β-amyloid accumulation. The first comparison was conducted between Group 1 and 2 revealing a significant accumulation of β-amyloid in the regions of the posterior cingulate gyrus. The posterior cingulate gyrus is involved in maintaining spatio-temporal orientation and memory functions, thanks to the connections with the parahippocampal cortex11. Involvement of the posterior cingulate gyrus is classic in patients with a typical clinical presentation of AD11. This result is also in agreement with the typical cerebral distribution of Aβ in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism from "ordinary” AD is hypothesized13. In support of this assumption, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral β-amyloid in the regions of the frontal lobe, are explanatory. On the basis of this evidence, we hypothesized that the CSF- / PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. The typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (executive dysfunctions19-20, deficits in design skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations to the tests that investigate the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar Aβ explains at most, a small part of the clinical-anatomical heterogeneity of AD13. In fact, in the frontal AD variant an increase in tangles of tau fibrils but not of amyloid plaques has been observed22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only then would they progress to the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some regions of the brain that are normally involved in pato This result is also in agreement with the cerebral distribution typical of Aβ in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism is hypothesized from that "typical" of AD13. In support of this hypothesis, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral β-amyloid in the regions of the frontal lobe (Fig.2), are explanatory. On the basis of this evidence, we hypothesized that the CSF-/PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients, behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. Typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (including executive dysfunctions19-20, deficits in planing skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations emerged at the tests investigating the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar Aβ explains at most a small part of the clinical-anatomical heterogeneity of AD13. Indeed, an increase in tau fibril tangles but not in amyloid plaques was observed in the frontal variant of AD.22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only afterwards they would progress towards the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some brain regions which generally, as mentioned, will normally be involved in the AD pathology in a subsequent time sequence. This vulnerability would be caused by the primary deposition of tau at the frontal level24-28. On the other hand, the frontal variant of AD is characterized by a pathological process that does not seem to remain limited to the frontal lobes for a long time18. Aggregation of Aβ would be driven by the total flux of neuronal activity while tau aggregation would depend on trans-neuronal diffusion, generating neurodegeneration models that coincide with specific functional networks that eventually lead to specific clinical phenotypes (AD variants)13. A better understanding of the factors that drive the heterogeneity of these clinical phenotypes can provide important insights into the mechanisms of the disease and have direct implications on the diagnosis and management of patients with emerging disease-specific therapies18. Finally, in our study, the third and fourth comparisons were conducted between Group 1 and Group 3 and between Group 2 and Group 3 respectively. Both groups showed a significant pattern of accumulation of cerebral β-amyloid widespread almost in all brain areas. This result is not surprising, in light of the fact that Group 3 probably configures the SNAP Group (suspected non-Alzheimer's pathophysiology), or a syndrome defined by normal levels of amyloid biomarkers (CSF- / PET-) but neurodegeneration patterns evident at MRI or FDG-PET29 imaging study. In fact, from 10% to 30% of clinically diagnosed ADs do not show neuropathological alterations of AD during an autopsy30 and a similar proportion has Aβ31 or CSF Aβ42 levels normal31-40. Thus the multi-domain anamnestic phenotype of dementia is not specific. it may be the product of other diseases as well as AD31. To date, SNAP remains a not yet well-defined nosological entity. The clinical diagnosis of AD is often "incorrect" but there are significant differences with regard to clinical progress, genetic susceptibility and progression of the pathology, which have crucial implications for a precise and correct diagnosis, for clinical management and effectiveness of clinical trials on drugs29. SNAP is a very frequent condition in clinically normal subjects > 65 years and appears to be age-related. A study found that the frequency of SNAP was 0% in the age group between 50-60 years while it reached 24% around the age of 8929. However, the literature does not agree. The main controversy in the literature is whether SNAP is an indipendent pathological entity or can evolve into AD41. Some researchers believe that SNAP should be included as an integral part of the AD spectrum; if so, the pathogenetic explanation of the amyloid-centric models of AD and the concept of preclinical AD42 are wrong and should therefore be reviewed. On the contrary, if SNAP is a different entity from AD, the amyloid-centric models of AD and preclinical AD42 are completely consistent with current knowledge. In both cases, multiple studies have shown that the pathogenesis of SNAP is linked to the deposition of tau fibrils, which justify cerebral neurodegeneration; it would then be Aβ, even in small quantities, to act as the biological driver of taupathy, and cause the "spread" of tau in a widespread manner throughout the brain43,44. Therefore a better understanding of the factors that guide the clinical and etiopathogenetic heterogeneity of AD studied thanks to methods such as flutemetamol-PET can provide direct implications on correct diagnosis and prognostic precision in clinical practice. Furthermore, understanding the different nosological entities in study allows a better stratification of the patients in the future trials and the management of emerging specific therapies for this disease

Effect of aging on cellular mechanotransduction

Aging is becoming a critical heath care issue and a burgeoning economic burden on society. Mechanotransduction is the ability of the cell to sense, process, and respond to mechanical stimuli and is an important regulator of physiologic function that has been found to play a role in regulating gene expression, protein synthesis, cell differentiation, tissue growth, and most recently, the pathophysiology of disease. Here we will review some of the recent findings of this field and attempt, where possible, to present changes in mechanotransduction that are associated with the aging process in several selected physiological systems, including musculoskeletal, cardiovascular, neuronal, respiratory systems and skin