Alzheimer’s disease due to loss of function: A new synthesis of the available data

Abstract

Alzheimer's Disease (AD) is a highly complex disease involving a broad range of clinical, cellular, and biochemical manifestations that are currently not understood in combination. This has led to many views of AD, e.g. the amyloid, tau, presenilin, oxidative stress, and metal hypotheses. The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts for the anomalies of the amyloid hypothesis, e.g. the curious pathogenicity of the Aβ42/Aβ40 ratio, the loss of Aβ caused by presenilin mutation, the mixed phenotypes of APP mutations, the poor clinical-biochemical correlations for genetic variant carriers, and the failure of Aβ reducing drugs. The amyloid-loss view accounts for recent findings on the structure and chemical features of Aβ variants and their coupling to human patient data. The lost normal function of APP/Aβ is argued to be metal transport across neuronal membranes, a view with no apparent anomalies and substantially more explanatory power than the gain-of-function amyloid hypothesis. In the loss-of-function scenario, the central event of Aβ aggregation is interpreted as a loss of soluble, functional monomer Aβ rather than toxic overload of oligomers. Accordingly, new research models and treatment strategies should focus on remediation of the functional amyloid balance, rather than strict containment of Aβ, which, for reasons rationalized in this review, has failed clinically.

Curcumin intervention for cognitive function in different types of people: A systematic review and meta‐analysis

“…A study showed that only free curcumin could reduce amyloid plaque burden and insoluble β‐amyloid peptide (Begum et al, ). Research included participants in a stage of dementia characterized by loss of neurons and senile plaque deposits outside neurons (Kepp, ). However, significant plasma levels of native curcumin, which prevents or reverses half the aggregation (IC50) of Aβ after 2‐ and 4‐g/day curcumin C3 complex (Ringman et al, ), could not be measured.…”

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

“…Growing evidence exists that native Aβ, which is produced during neuronal activity (Cirrito et al ., 2005), may subserve physiological functions (reviewed in Giuffrida et al ., 2010; Kepp, 2016). In particular, endogenous Aβ seems to be relevant for the control of synaptic activity and memory formation (Puzzo et al ., 2011; Piccini et al ., 2012), via the activation of α‐7‐nAChRs (Calabrese, 2001).…”

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

“…With respect to copper ions, some propose that AD is a disease of dietary copper deficiency (Klevay, 2008), while others propose it is caused by excess inorganic copper in the diet that can be treated using zinc therapy (Hoogenraad, 2011; Brewer, 2014) or a low-copper diet (Squitti et al, 2014b). Soluble, monomeric Aβ 1−x has even been proposed to possess a normal function in metal export, whereby metal-enrichment within plaques is associated with a loss of function (Kepp, 2016). Other potential physiological functions of Aβ 1−40/42 have been proposed, as an antimicrobial peptide (Soscia et al, 2010; Kumar et al, 2016) and as a cerebrovascular sealant (Atwood et al, 2003), although any role for copper ions in these contexts remains to be established.…”