Alzheimer's disease is becoming a well-known age-related condition, something that the average fellow in the street has actually heard of, unlike the vast majority of unpleasant things that happen to people as their bodies fail due to the accumulation of cell and tissue damage that causes aging. The widespread awareness of Alzheimer's disease is a function of the large-scale funding for research into its mechanisms; half of the National Institute on Aging budget is focused on this condition and all that needs to be learned to treat it effectively, and a correspondingly large chunk of private funding for neuroscience and the development of therapies for neurodegeneration is aimed in the same general direction.
We might think that Alzheimer's occupies the role of figurehead or rallying flag, a way to draw funds to the principal scientific goal of complete understanding of the biochemistry of the brain. This tends to be how things happen for large scale funding in medicine; three decades ago AIDS had much the same relationship with the broadest extent of viral research aimed at understanding first and therapies second. As is the case for Alzheimer's, it was an overlap of new capabilities in biotechnology, the existence of an effective advocacy community, and the need for funding to push forward the frontiers of scientific knowledge: numerous self-interests coming together.
Below you'll find links to a selection of recent Alzheimer's research. There is a lot going on, as it is a very complex condition, and the study of Alzheimer's really is the study of a very large slice of the biochemistry of the brain as a whole. One of the defining features of the field at present is a divergence of theories and exploration of alternative possible mechanisms beyond the accumulation of amyloid in brain tissues and the direct consequences of higher amyloid levels, meaning the creation of toxic and damaging molecules and the death or dsyfunction of brain cells. This search for alternatives is prompted by years of ongoing difficulties in the production of amyloid clearance therapies. Theorizing and early stage research are very cheap in comparison to later stages of development, and so always race ahead whenever obstacles arise.
Something else to bear in mind when reading the research in this field is that Alzheimer's appears to be almost as much a lifestyle disease as type 2 diabetes, though without the option to turn back at even comparatively late stages via aggressive lifestyle changes and fasting. People who get Alzheimer's are largely those who have been overweight and sedentary for decades: the same risk factors as is the case for diabetes and cardiovascular disease, and many of the underlying mechanisms may overlap in these and other age-related conditions. The degree to which Alzheimer's is an inevitability regardless of good health practices given a long enough life is an interesting question: everyone seems to accumulate more amyloid with age, but in the case of the oldest human beings it isn't the types of amyloid in the brain that cause death.
Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis.
Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.
Amyloid β (Aβ) plaque formation is a prominent cellular hallmark of Alzheimer's disease (AD). To date, immunization trials in AD patients have not been effective in terms of curing or ameliorating dementia. In addition, Presenilin 1 (PS1) genes are predictive for treatment of all AD patients. However most AD patients are of the sporadic form which partly explains the failures to treat this multifactorial disease.
Recently, pooled GWAS studies identified protein ubiquitination as one of the key modulators of AD. This revealed numerous proteins that strongly interact with ubiquitin (UBB) signaling, and pointing to a dysfunctional ubiquitin proteasome system (UPS) as a causal factor in AD. We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs). This suggests again a functional link between neurodegeneration of the AD type and loss of protein quality control by the UPS.
The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD.
As models of preclinical AD continue to develop, a challenge to the field is to reconcile the evidence of AD-related pathology found in a large number of cognitively normal (CN) elderly people with the notion of "healthy" or "successful" aging. This evidence seems to question the research practice of not considering possible presence of Alzheimer's pathology in CN elderly participants when including healthy elderly persons in cognitive studies. However, without the actual evidence to exclude Alzheimer's pathology, one can assume that some percentage of CN elderly subjects in such studies may represent preclinical AD. This problem has been occasionally recognized. It clearly requires a systematic change in approach, because subtle cognitive changes, reliance on cognitive strategies, and networks' reorganization that one would interpret as the effects of healthy aging might actually reflect the disease progression.
In the wake of failed amyloid-targeted drug trials and immune therapies, recent efforts are directed towards a broad range of alternative mechanisms of AD including mitochondrial dysfunction, metabolic stress, altered insulin signaling and, related to the 'vascular hypothesis of AD', cerebrovascular dysfunction. Accumulating evidence in fact supports the notion that cerebro- or neurovascular dysfunction may represent a primary initiator of a cascade of pathogenic events leading to neurodegeneration in AD. This mechanism takes on added significance when one considers increasing evidence linking sporadic AD with a number of vascular disorders including hypertension, hypercholesterolemia, obesity and type 2-diabetes.
Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia.
When proteins change their structure and clump together, formation of amyloid fibrils and plaques may occur. Such "misfolding" and "protein aggregation" processes damage cells and cause diseases such as Alzheimer's and type 2 diabetes. A team of scientists have now developed molecules that suppress protein aggregation and could pave the way for new treatments to combat Alzheimer's, type 2 diabetes and other cell-degenerative diseases. The scientists designed and studied 16 different peptide molecules in order to find out which of them are able to impede the cytotoxic "clumping" of the proteins amyloid beta (Aß) and islet amyloid polypeptide (IAPP), which are associated with Alzheimer's and type 2 diabetes.
"We used the novel approach of stimulating the endothelin B receptors by intravenous injection of IRL-1620 to prevent and repair the damage to the brain caused by Alzheimer's disease. Rats with AD showed impaired learning and memory and increased oxidative stress. We found that treatment with IRL-1620 reversed these effects. Intravenous injection with the drug improved memory deficit by 50 to 60 percent and reduced oxidative stress by 45 to 50 percent. We also found that treatment with IRL-1620 enhanced certain recovery processes within the AD-damaged brain, resulting in more new blood vessels and neuronal cells. This indicates reparative processes occurring in the damaged brain."