One of the puzzling aspects of sporadic Alzheimer\'s disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aβ), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aβ (1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aβ (1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aβ-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aβ (1-42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aβ homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.

Amyloid plaque formation in the brain is mainly responsible for the onset of Alzheimer\'s disease (AD). Structure-based peptides have gained importance in recent years, and rational design of the peptide sequences for the prevention of Aβ-aggregation and related toxicity is imperative. In this study, we investigate the structural modification of tetrapeptides derived from the hydrophobic C-terminal region of Aβ42 \"VVIA-NH2\" and its retro-sequence \"AIVV-NH2.\" A preliminary screening of synthesized peptides through an MTT cell viability assay followed by a ThT fluorescence assay revealed a peptide 13 (Ala-Ile-Aib-Val-NH2) that showed protection against Aβ-aggregation and associated neurotoxicity. The presence of the α-helix inducer \"Aib\" in peptide 13 manifested the conformational transition from cross-β-sheets to α-helical content in Aβ42. The absence of fibrils in electron microscopic analysis suggested the inhibitory potential of peptide 13. The HRMS, DLS, and ANS studies further confirmed the inhibitory activity of 13, and no cytotoxicity was observed. The structure-based peptide described herein is a promising amyloid-β inhibitor and provides a new lead for the development of AD therapeutics.

Alzheimer\'s disease (AD) is the most prevalent type of dementia; therefore, there is a high demand for therapeutic medication targeting it. In this context, extensive research has been conducted to identify molecular targets for drugs. AD manifests through two primary pathological signs: senile plaques and neurofibrillary tangles, caused by accumulations of amyloid-beta (Aβ) and phosphorylated tau, respectively. Thus, studies concerning the molecular mechanisms underlying AD etiology have primarily focused on Aβ generation and tau phosphorylation, with the anticipation of uncovering a signaling pathway impacting these molecular processes. Over the past two decades, studies using not only experimental model systems but also examining human brains have accumulated fragmentary evidences suggesting that REELIN signaling pathway is deeply involved in AD. Here, we explore REELIN signaling pathway and its involvement in memory function within the brain and review studies investigating molecular connections between REELIN signaling pathway and AD etiology. This review aims to understand how the manipulation (activation) of this pathway might ameliorate the disease\'s etiology.

OBJECTIVE: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated.
METHODS: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls.
RESULTS: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3.
CONCLUSIONS: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained.

BACKGROUND: The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers.
METHODS: Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau.
RESULTS: No clear evidence that Aβ40 or Aβ42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL.
CONCLUSIONS: Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau. In contrast, Aβ aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

Accurately diagnosing Alzheimer\'s disease (AD) and frontotemporal lobar degeneration (FTLD) is challenging due to overlapping symptoms and limitations of current imaging methods. This study investigates the use of [11C]PBB3 PET/CT imaging to visualize tau pathology and improve diagnostic accuracy. Given diagnostic challenges with symptoms and conventional imaging, [11C]PBB3 PET/CT\'s potential to enhance accuracy was investigated by correlating tau pathology with cerebrospinal fluid (CSF) biomarkers, positron emission tomography (PET), computed tomography (CT), amyloid-beta, and Mini-Mental State Examination (MMSE). We conducted [11C]PBB3 PET/CT imaging on 24 patients with suspected AD or FTLD, alongside [11C]PiB PET/CT (13 patients) and [18F]FDG PET/CT (15 patients). Visual and quantitative assessments of [11C]PBB3 uptake using standardized uptake value ratios (SUV-Rs) and correlation analyses with clinical assessments were performed. The scans revealed distinct tau accumulation patterns; 13 patients had no or faint uptake (PBB3-negative) and 11 had moderate to pronounced uptake (PBB3-positive). Significant inverse correlations were found between [11C]PBB3 SUV-Rs and MMSE scores, but not with CSF-tau or CSF-amyloid-beta levels. Here, we show that [11C]PBB3 PET/CT imaging can reveal distinct tau accumulation patterns and correlate these with cognitive impairment in neurodegenerative diseases. Our study demonstrates the potential of [11C]PBB3-PET imaging for visualizing tau pathology and assessing disease severity, offering a promising tool for enhancing diagnostic accuracy in AD and FTLD. Further research is essential to validate these findings and refine the use of tau-specific PET imaging in clinical practice, ultimately improving patient care and treatment outcomes.

Objective: To investigate the effects of photobiomodulation therapy (PBMT) at 660 and 810 nm on amyloid-beta (Aβ)42-induced toxicity in differentiated SH-SY5Y cells and to assess its impact on Aβ42 accumulation and cholinergic neurotransmission. Background: Alzheimer\'s disease (AD) is characterized by the accumulation of Aβ peptides, leading to neurodegeneration, cholinergic deficit, and cognitive decline. PBMT has emerged as a potential therapeutic approach to mitigate Aβ-induced toxicity and enhance cholinergic function. Methods: Differentiated neurons were treated with 1 μM Aβ42 for 1 day, followed by daily PBMT at wavelengths of 660 and 810 nm for 7 days. Treatments used LEDs emitting continuous wave light at a power density of 5 mW/cm2 for 10 min daily to achieve an energy density of 3 J/cm2. Results: Differentiated SH-SY5Y cells exhibited increased Aβ42 aggregation, neurite retraction, and reduced cell viability. PBMT at 810 nm significantly mitigated the Aβ42-induced toxicity in these cells, as evidenced by reduced Aβ42 aggregation, neurite retraction, and improved cell viability and neuronal morphology. Notably, this treatment also restored acetylcholine levels in the neurons exposed to Aβ42. Conclusions: PBMT at 810 nm effectively reduces Aβ42-induced toxicity and supports neuronal survival, highlighting its neuroprotective effects on cholinergic neurons. By shedding light on the impact of low-level light therapy on Aβ42 accumulation and cellular processes. These findings advocate for further research to elucidate the mechanisms of PBMT and validate its clinical relevance in AD management.

Neuroinflammation includes the activation of immune glial cells in the central nervous system, release pro-inflammatory cytokines, which disrupt normal neural function and contribute to various neurological disorders, including Alzheimer\'s disease (AD), Parkinson\'s disease, multiple sclerosis, and stroke. AD is characterized by various factors including amyloidogenesis, synaptic dysfunction, memory impairment and neuroinflammation. Lipopolysaccharide (LPS) constitutes a vital element of membrane of the gram-negative bacterial cell, triggering vigorous neuroinflammation and facilitating neurodegeneration. Lupeol, a naturally occurring pentacyclic triterpene, has demonstrated several pharmacological properties, notably its anti-inflammatory activity. In this study, we evaluated the anti-inflammatory and anti-Alzheimer activity of lupeol in lipopolysaccharide (LPS)-injected mice model. LPS (250ug/kg) was administered intraperitoneally to C57BL/6 N male mice for 1 week to induce neuroinflammation and cognitive impairment. For biochemical analysis, acetylcholinesterase (AChE) assay, western blotting and confocal microscopy were performed. AChE, western blot and immunofluorescence results showed that lupeol treatment (50 mg/kg) along with LPS administration significantly inhibited the LPS-induced activation of neuroinflammatory mediators and cytokines like nuclear factor (NF-κB), tumor necrosis factor (TNF-α), cyclooxygenase (COX-2) and interleukin (IL-1β). Furthermore, we found that LPS-induced systemic inflammation lead to Alzheimer\'s symptoms as LPS treatment enhances level of amyloid beta (Aβ), amyloid precursor protein (APP), Beta-site APP cleaving enzyme (BACE-1) and hyperphosphorylated Tau (p-Tau). Lupeol treatment reversed the LPS-induced elevated level of Aβ, APP, BACE-1 and p-Tau in the hippocampus, showing anti-Alzheimer\'s properties. It is also determined that lupeol prevented LPS-induced synaptic dysfunction via enhanced expression of pre-and post-synaptic markers like SNAP-23, synaptophysin and PSD-95. Overall, our study shows that lupeol prevents memory impairment and synaptic dysfunction via inhibition of neuroinflammatory processes. Hence, we suggest that lupeol might be a useful therapeutic agent in prevention of neuroinflammation-induced neurological disorders like AD.

Alzheimer\'s disease (AD) is a progressive neurodegenerative disease that falls under the umbrella of dementia and is characterized by the presence of enormously neurotoxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein inside the brain. AD remains an intractable global health challenge with limited therapeutic options. Early diagnosis, enabled by biomarkers and neuroimaging, is pivotal for optimizing treatment outcomes. Immunotherapeutic strategies, including monoclonal antibodies, active vaccination, and passive immunization, have been developed to target hallmark AD pathology, such as amyloid-beta aggregation. Here we summarized the emerging role of immunotherapies in the early stages of AD, shedding light on recent breakthroughs and clinical progress. Challenges, including treatment response variability and safety concerns, are discussed alongside evolving approaches, such as personalized immunotherapy and combinatorial treatments. This concise review underscores the promise of immunotherapies as a transformative approach to AD intervention, offering hope for a brighter future in the quest to combat this devastating neurodegenerative disease.

Ethics Review began a decade ago with a mission to identify ethical concerns that hold back innovation and to promote solutions that would move the field forward. Over this time, blood biomarkers for brain pathology and medications that treat that pathology promise to transform research and care. A central problem is that the evidence needed to guide test interpretation and practice is accumulating and there are unanswered questions. At the same time, people living with and at risk for dementia want access to their test results and involvement in their care. We promote dialog among diverse people across many institutions through collaboration with the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia.org). Over the years Ethics Review continues to publish these dialogs and solutions to overcome the paralysis of indecision and ethical concerns.