Metabolic resistance of Aß3pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab.

The amyloid ß peptide (Aß), starting with pyroglutamate (pE) at position 3 and ending at position 42 (Aß3pE-42), predominantly accumulates in the brains of Alzheimer's disease. Consistently, donanemab, a therapeutic antibody raised against Aß3pE-42, has been shown to be effective in recent clinical trials. Although the primary Aß produced physiologically is Aß1-40/42, an explanation for how and why this physiological Aß is converted to the pathological form remains elusive. Here, we present experimental evidence that accounts for the aging-associated Aß3pE-42 deposition: Aß3pE-42 was metabolically more stable than other Aßx-42 variants; deficiency of neprilysin, the major Aß-degrading enzyme, induced a relatively selective deposition of Aß3pE-42 in both APP transgenic and App knock-in mouse brains; Aß3pE-42 deposition always colocalized with Pittsburgh compound B-positive cored plaques in APP transgenic mouse brains; and under aberrant conditions, such as a significant reduction in neprilysin activity, aminopeptidases, dipeptidyl peptidases, and glutaminyl-peptide cyclotransferase-like were up-regulated in the progression of aging, and a proportion of Aß1-42 may be processed to Aß3pE-42. Our findings suggest that anti-Aß therapies are more effective if given before Aß3pE-42 deposition.

Depression in older adults and its associations with sleep and synaptic density.

BACKGROUND: Depression among older adults is a global concern, contributing to disability and overall illness burden. Understanding its trajectory, associated risk factors, and implications for mortality is essential for effective intervention. Moreover, the relationship between depression, sleep disturbances, and synaptic density in the ageing brain remains complex and poorly understood. METHODS: Using data from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort, comprising 6375 participants, we conducted comprehensive assessments of depression trajectories using generalized linear mixed models and mortality risks using Cox mixed-effects models. Generalized structural equation modelling was performed to explore longitudinal associations between sleep duration and depression. Lastly, associations between post-mortem synaptic density and depression were investigated. RESULTS: Our findings revealed that depression rates declined until age 80 before increasing again. Depression was associated with a 10 % increased risk of mortality in older adults. Reduced sleep was correlated with depression, and depression measured early in the study predicted future reduced sleep. Post-mortem analysis showed a global reduction in synaptic density associated with depression, particularly pronounced in the frontal lobe. LIMITATIONS: Limitations include recall bias, limiting generalizability due to dominantly including White British participants and difficulty in establishing causation between synaptic density and depression. CONCLUSION: Our study underscores the significance of addressing depression in older adults, not only for mental health but also for mortality risk and neurobiological health. Early detection and intervention strategies are crucial for improving outcomes in elderly populations, potentially mitigating adverse effects on sleep, synaptic density, cognitive health, and longevity.

Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response-A Rare Cause of Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. OBJECTIVES: We would like to highlight a rare but important differential of corticobasal syndrome. METHODS: A 78-year-old female had a 4-year history of predominantly right-hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right-sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post-mortem. RESULTS: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau-related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. CONCLUSIONS: Pick's disease can rarely present with clinical features of corticobasal syndrome.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Self-Reported Late-Life Hypertension Is Associated with a Healthy Cognitive Status and Reduced Alzheimer's Disease Pathology Burden.

Background: While mid-life hypertension represents a risk factor for the development of Alzheimer's disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria-even after controlling for sex, level of education and presence of APOEɛ4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.

Apolipoprotein-E genotyping in formalin-fixed and paraffin-embedded post-mortem brain tissue.

Formalin-fixed paraffin-embedded (FFPE) brain tissue held in tissue banks constitutes a valuable research resource, especially when associated with clinical annotations and longitudinal psychometric testing. Apolipoprotein-E (APOE) genotyping is important to fully characterise this resource, however older FFPE tissue may not be suitable for genotyping. We performed polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays on DNA extracted from post-mortem FFPE brain tissue ranging from 2-19 years old. A maximum of three years in paraffin was determined for robust APOE genotyping of FFPE tissue using PCR-RFLP which may suggest prolonged storage of fixed tissue as FFPE blocks may have deleterious effects on DNA.

Concomitant progressive supranuclear palsy and Lewy body pathology presenting with circumscribed visual memory loss: A clinicopathological case.

A 70-year-old man presented to the clinic with impairment of visual memory and marked predominantly right sided mesial temporal lobe atrophy on imaging. He died 6 years following symptom onset and neuropathological examination showed concomitant progressive supranuclear palsy and Lewy body pathology. Although he did not fulfil clinical criteria for either condition at presentation, we propose that interactions between the two pathologies in mesial temporal regions could result in this atypical clinical phenotype.