A beta 1-40, a major component of Alzheimer's disease cerebral amyloid, is present in the cerebrospinal fluid and remains relatively soluble at high concentrations (less than or equal to 3.7 mM). Thus, physiological factors which induce A beta amyloid formation could provide clues to the pathogenesis of the disease. It has been shown that human A beta specifically and saturably binds zinc. Here, concentrations of zinc above 300 nM rapidly destabilized human A beta 1-40 solutions, inducing tinctorial amyloid formation. However, rat A beta 1-40 binds zinc less avidly and is immune to these effects, perhaps explaining the scarcity with which these animals form cerebral A beta amyloid. These data suggest a role for cerebral zinc metabolism in the neuropathogenesis of Alzheimer's disease.

Huntington's disease (HD) is a dominant neurodegenerative disorder caused by expansion of a CAG repeat in the gene encoding huntingtin, a protein of unknown function. To distinguish between "loss of function" and "gain of function" models of HD, the murine HD homolog Hdh was inactivated by gene targeting. Mice heterozygous for Hdh inactivation were phenotypically normal, whereas homozygosity resulted in embryonic death. Homozygotes displayed abnormal gastrulation at embryonic day 7.5 and were resorbing by day 8.5. Thus, huntingtin is critical early in embryonic development, before the emergence of the nervous system. That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein. To elucidate the molecular basis of HD, we extended the polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an expanded human HD CAG repeat, creating mutant HdhneoQ50 and HdhQ50 alleles that express reduced and wild-type levels of altered huntingtin, respectively. Mice homozygous for reduced levels displayed characteristic aberrant brain development and perinatal lethality, indicating a critical function for Hdh in neurogenesis. However, mice with normal levels of mutant huntingtin did not display these abnormalities, indicating that the expanded CAG repeat does not eliminate or detectably impair huntingtin's neurogenic function. Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism.

Summary Background Idiopathic Parkinson’s disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders. Methods Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2·6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis. Findings 167 patients were assessed. Image-based classification for idiopathic Parkinson’s disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV). Interpretation Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials. Funding National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.

Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.

The heterogeneous precipitates of A␤ that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that A␤1-40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where A␤ is most likely to precipitate. We now present evidence that the zinc-induced precipitation of A␤ is mediated by a peptide dimer and favored by conditions that promote ␣-helical and diminish ␤-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behavior in vitro. Zincinduced A␤ aggregation was dependent upon the presence of NaCl, was enhanced by ␣-helical-promoting solvents, but was abolished when the peptide stock solution was stored frozen. The A␤ aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, A␤ aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-A␤ interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible A␤ assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of A␤ deposit in the disease.The pathological hallmark of Alzheimer's disease is the abundant accumulation in the brain of A␤, a 39 -43-amino acid peptide, as morphologically heterogeneous deposits in the neuropil (senile plaques) and cerebral blood vessels (congophilic angiopathy) (1, 2). A␤ is a soluble component of cerebrospinal fluid where it is found in concentrations in the low nanomolar range (3-5). Many studies now indicate that synthetic A␤ becomes toxic to cultured neuronal cells when in a specific ␤-sheet conformation that involves incubating the synthetic peptide in a aqueous solution over time periods of days to weeks (6 -14). Whereas the ␤-sheet conformation of the peptide is found in highly insoluble fibrillar amyloid deposits in Alzheimer's disease, a substantial proportion of A␤ precipitates into nonfibrillar deposits that can be resolubilized by extraction into aqueous solvents (15).We have recently reported that A␤ itself specifically and saturably binds zinc, manifesting high affinity binding (K D ϭ 107 nM) with a 1:1 (zinc:A␤) stoichiometry and low affinity binding (K D ϭ 5.2 M) with a 2:1 stoichiometry (16). This binding is probably histidine-mediated since it is abolished by acidic pH (no binding at pH 6). The zinc-binding site was mapped to a stretch of contiguous residues between positions 6 -28 of the A␤ sequence. Occupation of the zinc-binding site, which straddles the lysine 16 position of ␣-secretase cleavage (17, 18), inhibits ␣-secretase type (tryp...

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as “an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern,” based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5–267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6–1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as “Low CTE” or “High CTE” for use in future clinical, pathological, and molecular studies.

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