The open access paper noted here is a fairly concise tour through current thinking on the role of amyloid-β in Alzheimer's disease. Amyloids are solid deposits that appear in aged tissues, a few specific proteins that can misfold or become altered in ways that cause them to clump together and precipitate from solution into fibrils and other structures. Either the amyloid itself or, as in the case of amyloid-β, the surrounding biochemistry prompted by its existence causes harm to cells. Since amyloids are created as a side-effect of the normal operation of cellular metabolism, and since they do in fact cause harm, they can be considered one of the root causes of aging. Why they are found in old tissues rather than young tissues is may be primarily a consequences of failing maintenance systems: problems in the drainage or filtration of cerebrospinal fluid; the progressive dysfunction of immune cells responsible for clearing out unwanted metabolic waste; the progressive failure of recycling mechanisms in long-lived cells.
Given this, it is interesting to consider that the high-profile efforts to reduce levels of amyloid-β in Alzheimer's patients, largely through immunotherapies, were one of the earliest forms of significant work on rejuvenation - though not carried out with that intent. It continues to be the most aggressively funded of all such research, and still not with the intent of rejuvenation, though any sufficiently safe and comprehensive treatment could be repurposed for that use. Unfortunately it has proven very challenging to safely remove amyloid-β through the methodologies chosen to date: despite dozens of clinical trials since the turn of the century, only last year was real progress made with aducanumab. Lack of progress breeds a diversity of other approaches, and so despite the central position of amyloid-β in the consensus on how Alzheimer's progresses and causes harm, many competing views of the condition have come into being over the past decade. Some researchers now focus on inflammation, immune dysfunction, and microbial infections. Others focus on tau protein and neurofibrillary tangles, raising the profile of Alzheimer's as a tauopathy. Still more investigate age-related declines in the drainage of cerebrospinal fluid.
Clearance of amyloid-β remains the primary strategy and where most of the funding goes. It does seem fairly clear that Alzheimer's, like most of aging, has multiple contributing causes. Numerous theories of causation other than amyloid-β have a good deal of solid evidence backing them, particularly tau and microbial infection. Given the challenges inherent in analyzing the complexities of the disease, however, it will require success in removing at least one of the causes to make any serious headway in discussions of either (a) the relative size of various contributions, or (b) which are primary causes versus secondary consequences that cause their own problems.
Nascent protein chains, emerging from the ribosomes, need to fold properly into unique 3D structures, eventually translocate and then assemble into stable, functionally flexible complexes. In the crowded cellular environment, newly synthesized polypeptide chains are at risk of misfolding, forming stable, toxic aggregates. These species may accumulate in aged animal cells, especially in neurons and can cause cellular damage inducing cell death. Aggregation of specific proteins into protein inclusions and plaques is characteristic for many neurodegenerative diseases (NDDs), including Alzheimer's disease (AD). Molecular pathological classification of neurodegenerative diseases is based on the presence of these pathologically altered, misfolded proteins in the brain as deposits. The combination of proteinopathies is also frequent.
What is the mechanism of formation of toxic protein aggregates in a living cell? Proteins are structurally dynamic and thus constant surveillance of the proteome by integrated networks of chaperones and protein degradation machineries (including several forms of autophagy) are required to maintain protein homeostasis (proteostasis). NDDs are considered mostly as pathologies of disturbed protein homeostasis. The proteostasis network declines during aging, triggering neurodegeneration and other chronic diseases associated with toxic protein aggregation. In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds. In AD, toxic β-amyloid (Aβ) and hyperphosphorylated Tau (pTau) aggregates may interact with subcellular organelles of the neurons, trigger neuronal dysfunction and apoptosis that lead to memory decline and dementia.
Aging per se is the most important factor of AD and several other neurodegenerative diseases, "the neurobiology of aging and AD is walking down the same road". AD could be seen as a "maladaptive interaction between human brain evolution and senescence". Other authors hypothesized that formation of aggregated proteins might be a protective strategy of the aging neurons. There are numerous hypotheses for understanding the pathogenesis of AD, owing to the multifactorial character of the disease. Some of them (disturbance of the cholinergic system; hypoperfusion, hypoxia in the brain; Ca2+-signalization problems; neuroinflammation; mitochondrial dysfunction; chronic endplasmic reticulum stress and protein misfolding; decreased Aβ-clearance, etc.) are not controversial and could be unified into a general broad hypothesis. The common nominator of these hypotheses is the important role of Aβ in the pathogenesis of AD.
The conventional view of AD is that much of the AD-pathology is driven by an increased load of Aβ in the brain of patients ("amyloid hypothesis"). During the last 15 years many therapeutic strategies were based on lowering Aβ in the brain. Up to now, most of the strategies have failed in clinical trials and the relevance of the amyloid hypothesis has often been questioned. Very recent results show that pathophysiological changes begin many years before clinical manifestation of AD and the disease is a multifaceted process. The core of the amyloid hypothesis stays on and novel clinical trial strategies may hold promise.
In the present review article, we summarize the physiological functions of amyloid precursor protein (APP) and the role of amyloid fragments in adult brain. Then we give a short summary on the genetic background of AD, the interaction of Aβ peptides with subcellular organelles, the pathways of Aβ clearance from the brain, the role of neuroinflammation, brain circulation and the blood-brain-barrier (BBB) in the AD pathogenesis. Finally, we discuss very shortly the major trends in drug discovery and the possibilities for prevention and treatment of AD.