• Activating transcription factors
• Alzheimer's disease
• Apoptosis

• Aducanumab
• Alzheimer's disease
• Blood-brain barrier
• Immunotherapy
• Lecanemab

• Alzheimer’s disease
• BACE1
• BACE1 inhibitors
• age-related diseases
• aging

• Alzheimer’s disease
• amyloid-β
• blood-brain barrier
• drug delivery
• nanomedicine
• nanotheranostics
• neurodegeneration
• polymeric nanoparticles

• Acetylcholine
• Alzheimer’s disease
• Amyloid
• Dementia
• Hypothesis
• Management
• Neurodegenerative
• Tau protein

Alzheimer’s disease (AD) is still a major public health challenge without an effective treatment to prevent or stop it. Routinely used acetylcholinesterase inhibitors and memantine seem to slow disease progression only to a limited extend. Therefore, many investigations on new drugs and other treatment modalities are ongoing in close association with increasing knowledge of the pathophysiology of the disease. Here, we review the studies about the new treatment modalities in AD with a classification based on their main targets, specifically pathologic structures of the disease, amyloid and tau, neural network dysfunction with special interest to the regulation of gamma oscillations, and attempts for the restoration of neural tissue via regenerative medicine. Additionally, we describe the evolving modalities related to gut microbiota, modulation, microglial function, and glucose metabolism.

• Alzheimer’s disease treatment
• Anti-amyloid
• Anti-tau
• Gamma oscillations
• Stem cell therapy

• Alzheimer’s disease - complicated disease - anti-AD drugs
• Hypothesis about AD

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is complex and progressive; it has not only threatened the health of elderly people, but also burdened the whole social medical and health system. The available therapy for AD is limited and the efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the design and development of efficacious and safe anti-AD agents has become a hotspot in the field of pharmaceutical research. Due to the multifactorial etiology of AD, the multitarget-directed ligands (MTDLs) approach is promising in search for new drugs for AD. Tacrine, which is the first acetylcholinesterase (AChE) inhibitor, has been selected as the ideal active fragment because of its simple structure, clear activity, and its superiority in the structural modification, thus it could be introduced into the overall molecular skeletons of the multi-target-directed anti-AD agents. In this review, we have summarized the recent advances (2012 to the present) in the chemical modification of tacrine, which could provide the reference for the further study of novel multi-target-directed tacrine derivatives to treat AD.

• AChE inhibitors
• Alzheimer’s disease
• multitarget-directed
• tacrine

• Alzheimer’s disease
• BACE-1
• blood–brain barrier
• endothelium
• β-amyloid

• Age-related macular degeneration
• Angiogenesis
• Choroidal neovascularisation
• Lysosomes
• Mitochondria
• Retinal degeneration
• Retinal pigment epithelium
• β-secretase

• Amyloid-β precursor protein
• Amyloidogenesis
• BACE1
• N2a cells
• PPARγ
• Tripchlorolide

• alzheimer's disease
• antioxidants
• β-amyloid anti-aggregation properties
• cholinesterase inhibitors
• inhibitors of β-secretase
• inhibitors of monoamine oxidase a/b
• multi-target-directed ligands
• neuroprotective properties.

• Alzheimer Disease/drug therapy
• Alzheimer Disease/enzymology
• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/chemistry
• Amyloid beta-Peptides/metabolism
• Animals
• Drug Discovery/methods
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Enzyme Inhibitors/therapeutic use
• Humans
• Neuroprotective Agents/chemistry
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Protein Aggregates/drug effects

• Aging
• Alzheimer's disease
• anti-amyloid therapy
• dementia
• dystrophic neurites
• neurodegenerative disorders
• neuroplasticity
• senile plaques
• synaptic dysfunction

Alzheimer’s disease (AD) is one of the most complicated progressive neurodegeneration diseases that involve many genes, proteins, and their complex interactions. No effective medicines or treatments are available yet to stop or reverse the progression of the disease due to its polygenic nature. To facilitate discovery of new AD drugs and better understand the AD neurosignaling pathways involved, we have constructed an Alzheimer’s disease domain-specific chemogenomics knowledgebase, AlzPlatform (www.cbligand.org/AD/) with cloud computing and sourcing functions. AlzPlatform is implemented with powerful computational algorithms, including our established TargetHunter, HTDocking, and BBB Predictor for target identification and polypharmacology analysis for AD research. The platform has assembled various AD-related chemogenomics data records, including 928 genes and 320 proteins related to AD, 194 AD drugs approved or in clinical trials, and 405 188 chemicals associated with 1 023 137 records of reported bioactivities from 38 284 corresponding bioassays and 10 050 references. Furthermore, we have demonstrated the application of the AlzPlatform in three case studies for identification of multitargets and polypharmacology analysis of FDA-approved drugs and also for screening and prediction of new AD active small chemical molecules and potential novel AD drug targets by our established TargetHunter and/or HTDocking programs. The predictions were confirmed by reported bioactivity data and our in vitro experimental validation. Overall, AlzPlatform will enrich our knowledge for AD target identification, drug discovery, and polypharmacology analyses and, also, facilitate the chemogenomics data sharing and information exchange/communications in aid of new anti-AD drug discovery and development.

The β-amyloid precursor protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) of Alzheimer's disease. However, the normal function of APP remains largely unknown. This article reviews studies on the structure, expression and post-translational processing of APP, as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms.

This article reviews studies on the structure, expression and post-translational processing of β-amyloid precursor protein (APP), as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms.

• Alzheimer's disease
• amyloid precursor protein
• growth factor
• heparin
• neurotrophic
• receptor

Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer’s disease. We have now attached a retro-inverted version of the HIV protein transduction domain ‘TAT’ to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH₂) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer’s disease.

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Amyloid/chemistry
• Amyloid/metabolism
• Amyloid beta-Peptides/metabolism
• Amyloid beta-Peptides/toxicity
• Amyloid beta-Protein Precursor/genetics
• Animals
• Blood-Brain Barrier/metabolism
• Cell Line
• Cells, Cultured
• Disease Models, Animal
• Female
• Inflammation/metabolism
• Male
• Mice
• Mice, Transgenic
• Microglia/drug effects
• Microglia/metabolism
• Neurogenesis/drug effects
• Neurogenesis/genetics
• Oxidation-Reduction
• Oxidative Stress
• Peptides/metabolism
• Peptides/pharmacology
• Permeability
• Plaque, Amyloid
• Protein Binding
• Protein Multimerization/drug effects

• angiogenesis
• β-secretase
• lipofuscin
• retina
• retinal pigment epithelium

• Amyloid Precursor Protein Secretases/antagonists & inhibitors
• Amyloid Precursor Protein Secretases/deficiency
• Animals
• Aspartic Acid Endopeptidases/antagonists & inhibitors
• Aspartic Acid Endopeptidases/deficiency
• Choroidal Neovascularization/pathology
• Enzyme Inhibitors/administration & dosage
• Female
• Gene Silencing
• Lipofuscin/metabolism
• Lysosomes/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Retina/pathology

• P30 EY005722 NEI NIH HHS
• UL1 TR000064 NCATS NIH HHS
• EY007739 NEI NIH HHS
• R01 EY019038 NEI NIH HHS
• EY 012606 NEI NIH HHS
• R01 EY011286 NEI NIH HHS
• EY019038 NEI NIH HHS
• R01 EY007739 NEI NIH HHS
• AG020206 NIA NIH HHS
• EY019688 NEI NIH HHS
• AG18454 NIA NIH HHS
• R01 EY019688 NEI NIH HHS
• EY018358 NEI NIH HHS
• R01 AG018454 NIA NIH HHS
• R01 EY018358 NEI NIH HHS

Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid-β peptides (Aβ) level contributes to aggregations of the peptide and subsequent development of the disease. The major constituent of these amyloid peptides is the 1 to 40–42 residue peptide (Aβ₄₀₋₄₂) derived from amyloid protein precursor (APP). Most likely, reducing Aβ levels in the brain may block both its aggregation and neurotoxicity and would be beneficial for patients with AD. Among the several possible ways to lower Aβ accumulation in the cells, we have selectively chosen to target the primary step in the Aβ cascade, namely, to reduce APP gene expression. Toward this end, we engineered specific SOFA-HDV ribozymes, a new generation of catalytic RNA tools, to decrease APP mRNA levels. Additionally, we demonstrated that APP-ribozymes are effective at decreasing APP mRNA and protein levels as well as Aβ levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD.

• Alzheimer Disease/drug therapy
• Alzheimer Disease/metabolism
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Brain/drug effects
• Brain/metabolism
• Cysteine/administration & dosage
• Cysteine/analogs & derivatives
• Disease Models, Animal
• Galactose/adverse effects
• Glycosylation/drug effects
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress/drug effects

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Currently available therapies are symptomatic but do not alter underlying disease progression. Immunotherapeutic approaches such as anti Aβ peptide active vaccination trials have had limited success to date. Intravenous immunoblobulin (IVIg) is widely used in immune-mediated neurological disorders such myasthenia gravis and Guillain-Barre syndrome. These preparations have been obtained from the pooled plasma of healthy human donors and contain natural anti-amyloid antibodies and are well tolerated. A small pilot study of passive immunotherapy using IVIg has suggested cognitive improvement. A multicenter phase III trial is ongoing and will determine whether or not this treatment can ameliorate cognitive deficits in mild-to-moderate AD. Here, we briefly review the pathogenic role of amyloid and tau in AD, as well as immunotherapeutic efforts to date. We also summarize what is known about naturally occurring anti-Aβ and tau antibodies in IVIg with a view toward explaining potential mechanisms underlying their therapeutic effects.

• Alzheimer’s
• amyloid oligomers
• conformation antibodies
• immunotherapy
• tau oligomers