Targeting ß-amyloid by the A2V Aß variant: a novel disease-modifying strategy for the treatment of Alzheimer’s disease (original) (raw)
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Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant
Journal of Alzheimer's Disease, 2006
Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40-42 residues amyloid β (Aβ) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid βprotein precursor (AβPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Aβ E22Q. Subsequent identification of additional mutations in the AβPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the middle of Aβ, residues Efrat Levy Blas Frangione Aβ21-23, are predominantly vasculotropic, those found amino-or carboxyl-terminal to the Aβ sequence within AβPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions aminoor carboxyl-terminal to Aβ lead to either greater Aβ production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Aβ1-42. Substitutions in the center of Aβ facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AβPP, indicating that other factors may alter Aβ production, conformation, and/or clearance initiating the disease process.
Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid-β
Scientific Reports, 2016
We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6 A2V), linked to the HIVrelated TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6 A2V TAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6 A2V TAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the Aβ A2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6 A2V TAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. Alzheimer's disease (AD) is the most common form of dementia in the elderly. Its clinical course is slow but irreversible since no disease-modifying treatments are currently available. As a result, this illness has a huge socio-sanitary impact and designing of effective therapies is considered a public health priority. A central pathological feature of AD is the accumulation of misfolded Amyloid-beta (Aβ) peptides in the form of oligomers and amyloid fibrils in the brain 1-3. It has been advanced that aggregated Aβ species, particularly oligomeric assemblies, trigger a cascade of events that lead to hyperphosphorylation, misfolding and assembly of the tau protein with formation of neurofibrillary tangles and disruption of the neuronal cytoskeleton, widespread synaptic loss and neurodegeneration. According to this view, altered Aβ species are the primary cause of AD and the primary target for therapeutic intervention 3,4. Aβ peptides derive from proteolytic processing of a large (695/770 amino acids) type 1 transmembrane glycoprotein known as amyloid beta precursor protein (APP). APP is cleaved at the N-terminus of the Aβ domain by β-secretase, forming a large, soluble ectodomain (sAPPβ) and a 99-residue, membrane-retained C-terminal fragment (C99). Subsequently, γ-secretase cleaves C99 to release Aβ with different carboxyl termini, including Aβ 40, Aβ 42 and other minor species 5. APP may undergo an alternative, non-amyloidogenic processing where the protein is cleaved within the Aβ domain by α-secretase, forming a soluble ectodomain (sAPPα) and an 83-residue C-terminal fragment (C83) 5,6. We identified a novel mutation in the APP gene resulting in A-to-V substitution at codon 673, corresponding to position 2 in the Aβ sequence 7. Studies on biological samples from an A673V homozygous carrier, and cellular
Journal of Clinical Medicine
The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer’s disease: Down syndrome-associated Alzheimer’s disease in (DSAD) and Autosomal Dominant Alzheimer’s disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.
Genetics of early-onset Alzheimer dementia
Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies.
ALZHEIMER'S RESEARCH & THERAPY_AD GENETICS DEBATE_2013.pdf
Several genetic variants have been shown to modulate the risk of developing Alzheimer's disease (AD). Largescale, international eff orts in the fi eld of AD genetics have led to the identifi cation of AD forms showing familial clustering, which are caused by inherited single-gene mutations. Familial AD (FAD) is generally characterized by an early (<60 years) or very early (30 to 50 years) age at onset and accounts for less than 5% of all of the AD cases . A signifi cant proportion of FAD cases is caused by autosomal dominant, highly penetrant mutations in at least three diff erent genes, that is, amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). At the time of writing, the Alzheimer Disease & Frontotemporal Dementia Mutation database lists a total of 231 FAD-causing pathogenic mutations (33 pathogenic variants for APP, 185 for PSEN1, and 13 for PSEN2) [2].
Alzheimer\u27s: A Tale of Two Diseases
2017
Alzheimer’s disease (AD) is unique in that multiple paths can lead to its manifestation. There are numerous risk factors that increase the susceptibility to AD and a vast number of combinations may lead to its acquisition. Additionally, the underlying mechanism by which the illness manifests itself could possibly differ amongst varying patients. It is my contention that early on-set Alzheimer’s can be categorized as a unique illness in respect to late on-set AD, due to vastly different etiologies although symptoms are similar. It will be demonstrated that early on-set AD is largely a genetically based etiology with little that can be done for prevention. Late on-set AD however, tends to be due to chronic environmental factors which preventative measures could have avoided. In addition, just as there is a need to have fuller characterization of Dementia I will defend the position that the treatment of AD as the more general term of two more precise illnesses is beneficial and the eth...
The genetics of Familial Alzheimer’s Disease
AGE, 1988
Familial Alzheimer Disease (FAD) presents as a diagnostically unique disorder having an autosomal dominant form of Inheritance with an agedependent penetrance. Recent mapping of the FAD and beta.amylold protein (AP) genes to human chromosome 21 has raised questions as to the role of AP In the development of FAD. The Involvement of gene(s) on chromosome 21 In FAD was suggested because of the observation that In. dlvlduals with Down Syndrome (DS) over the age of 40 all develop the neuropathological changes associated with AD. Refinement of the AP mapping has eliminated this locus as being the site of the primary genetic defect causing FAD. This leads to speculation as to the mutation(s) responsible for and the role of gene(s) on chromosome 21 Involved In FAD.