Β-amyloid Hypothesis Research Articles

Kismet/CHD7/CHD8 and Amyloid Precursor Protein-like Regulate Synaptic Levels of Rab11 at the Drosophila Neuromuscular Junction.

The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer's disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD.

Mechanism of neurodegeneration through tau and therapy for Alzheimer's disease

In Alzheimer's disease (AD), β-amyloid deposition and neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau fibrils, are considered to be major pathologic features. Evidence from the genetic studies of familial AD has given rise to the β-amyloid hypothesis in which β-amyloid is proposed as the cause of AD; thus, the reduction of β-amyloid has been viewed as a potential therapeutic target for AD.1 However, most studies targeting β-amyloid have failed in phase III clinical trial, as discussed extensively elsewhere.2 A major explanation for such failures may be that such therapies have been tested in patients with early- to mid-stage AD, when disease progression is already relatively advanced. In fact, when first AD symptoms are reported or detected, it seems that damage is irreversible and not amenable to slowing down or blockade. Accordingly, researchers are attempting to identify very early stages of disease, that may be therapeutically targetable; that is, they are now seeking an early window of therapeutic opportunity. Even so, this approach depends on differentiating between the trigger and the bullet in AD and their relationship to β-amyloid. At the same time, researchers are becoming aware that an alternative target for halting clinical progression, even in early to moderate AD, may be necessary.

Feasibility of β-sheet breaker peptide-H102 treatment for Alzheimer's disease based on β-amyloid hypothesis.

β-amyloid hypothesis is the predominant hypothesis in the study of pathogenesis of Alzheimer's disease. This hypothesis claims that aggregation and neurotoxic effects of amyloid β (Aβ) is the common pathway in a variety of etiological factors for Alzheimer's disease. Aβ peptide derives from amyloid precursor protein (APP). β-sheet breaker peptides can directly prevent and reverse protein misfolding and aggregation in conformational disorders. Based on the stereochemical structure of Aβ1-42 and aggregation character, we had designed a series of β-sheet breaker peptides in our previous work and screened out a 10-residue peptide β-sheet breaker peptide, H102. We evaluated the effects of H102 on expression of P-tau, several associated proteins, inflammatory factors and apoptosis factors, and examined the cognitive ability of APP transgenic mice by behavioral test. This study aims to validate the β-amyloid hypothesis and provide an experimental evidence for the feasibility of H102 treatment for Alzheimer's disease.

Potential Blood Biomarkers in Age-related Cerebral Small Vessel Disease

Cerebral small vessel disease is a general term used to reflect clinical, radiological, or pathological phenomena attributed to small vessels of the brain, including small arteries and arterioles but also capillaries and small veins. Age-related cerebral small vessel disease is one of its most common subtypes, and is related to age and vascular risk factors. The consequences of age-related cerebral small vessel disease are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large hemorrhages, and microbleeds, which are an important cause of stroke, dementia, and age-related disability. The causes or pathogenesis underlying these phenotypes are not completely understood, and biomarkers to predict the risk and progression are highly needed. This review aims to summarize recent knowledge regarding potential blood biomarkers in age-related cerebral small vessel disease according to the different mechanisms: endothelial dysfunction, inflammation, and β-amyloid hypothesis.

The β-Amyloid Hypothesis in Alzheimer's Disease: Seeing Is Believing.

Human amyloid imaging is now on the verge of being approved by the FDA for routine clinical use. Although this procedure may prove to be tremendously valuable once it is incorporated into the routine clinical workup of dementia patients, currently, this imaging procedure is not without its critics. The debate on the utility of human amyloid imaging may be just a part of the validation process for this new technology. Ten years ago, AD and “aging” researchers overwhelmingly celebrated the first [11C]PIB human amyloid imaging that demonstrated the feasibility to “see” the Aβ plaques in the living human brain and the corroboration of the Aβ hypothesis. Now, the F-18 Aβ-specific agents will take this imaging tool to the next level, benefiting a large number of patients. This is an exciting time for clinicians and scientists who may further examine or clarify the Aβ hypothesis and correlate its relationship to AD by “peeking” into the living human brain from various angels. The amyloid-specific imaging will also provide a renewed scientific vigor in selecting and monitoring patients enrolled in clinical trials for AD drugs specifically targeting Aβ deposition in the brain.

Biomarkers to Advance Drug Development for Alzheimer‘s Disease

There is a sense of excitement and anticipation that drugs based on the β-amyloid hypothesis of Alzheimer’s disease (AD) may significantly reduce progression of the disease. However, without appropriate biomarkers, potentially effective drugs may actually fail to demonstrate efficacy owing to difficulties in choosing a proper dose and difficulty in detecting improved clinical outcomes in short trials. Both hypothesis- and discovery-based approaches, including high-throughput proteomic profiling, should be applied for discovery of biomarkers to better understand the action of novel therapies on their targets and on the molecular pathology of the disease. It is also imperative to identify antecedent markers, without which, patients with AD will be prescribed drugs that may prolong a life of slowly progressing dementia. Where we look for novel AD biomarkers and how we discover them is the subject of this perspective.

β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease

Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Abeta in synaptic degeneration awaits confirmation. In this study, we show that Abeta reduction by active or passive Abeta immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Abeta in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of Abeta immunotherapy as a treatment approach for this disease.

Alzheimer's disease: β-amyloid hypothesis strengthened!

Alzheimer's disease (AD) is a devastating progressive human neurodegenerative disease that debilitates millions of elderly people, presenting an enormous burden on the families of those affected, as well as society in general. The accumulation of β-amyloid (Aβ) plaques has been one of the most prominent mechanisms proposed to underlie the neurodegeneration that leads to the phenotypical abnormalities seen in AD. Nevertheless, the direct causal link between Aβ and impaired neuronal function and memory has been debated. Three recent papers from independent laboratories now suggest that Aβ is indeed the culprit.

Membrane alterations as causes of impaired signal transduction in Alzheimer's disease and aging

Changes in cell-membrane composition in normal aging and in Alzheimer's and other age-related diseases appear to result in impaired neurotransmitter-triggered signal transduction. The impaired signal transduction seems to be related to dysfunctions in the coupling of G proteins to their receptors and effectors. Direct demonstration of altered physiochemical properties of brain tissue of patients with Alzheimer's disease has been achieved by small-angle X-ray diffraction. In this disease, thinner membranes correlate with a 30% decrease in moles of cholesterol: phospholipid. Such changes can affect directly the coupling and uncoupling properties of G proteins, and can account for signal transduction deficits. These findings offer a complementary alternative to the β-amyloid hypothesis, and an opportunity to consider new types of therapeutic interventions.