A Unifying Hypothesis for Alzheimer’s Disease: From Plaques to Neurodegeneration

Abstract

Evidence suggests that amyloidβ is highly toxic to synapses in a phosphoTau-dependent manner. Here I present an hypothesis that links previous evidence from the first rise of amyloidβ through to Tau tangles and neurodegeneration. In the immediate vicinity of plaques, concentrated soluble amyloidβ occurs in equilibrium with deposited forms. Initially, plaques cover only a small percentage of brain volume. Microglia, by efficiently removing damaged synapses, may prevent spread of damage along the axon, restricting damage to the immediate vicinity of plaques. However, as plaque load increases, as seen in Alzheimer's disease, an individual axon may suffer multiple points of damage, leading to dissociation of Tau, formation of a tangle and loss of the axon. As more axons suffer this fate, the network eventually degenerates. According to this hypothesis, the degree of plaque load that an individual can tolerate would depend on the efficiency of his/her microglia in removing amyloidβ-damaged synapses and the distribution of plaques, relative to axon trajectories, would determine the eventual cognitive symptoms.3 influencing disease progression and 4. the substantial variability in plaque load that individuals can carry before neurodegeneration and cognitive deficits occur.

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

“…The correlational analyses indicated that Ab42 fraction was positively correlated with pTau and Iba1 fraction, while memory functions (number of visits to the goal region) were negatively correlated with Ab and pTau fractions. These findings in this mouse AD model represent characteristics of human AD pathological findings and support the amyloid cascade theory of AD, in which accumulation of pathogenic Ab induces amyloid plaques, hyperphosphorylation of tau (tauopathy), and microglial activation (Hardy and Selkoe, 2002;Selkoe and Hardy, 2016;Sasaguri et al, 2017;Edwards, 2019;Hashimoto et al, 2019).…”

“…Ab42 is more neurotoxic due to its higher hydrophobicity, which promotes oligomerization and aggregation (Blennow and Zetterberg, 2018). Ab deposition also induces microglial activation, which may ameliorate neurodegeneration due to Ab accumulation (Deczkowska et al, 2018;Edwards, 2019). Accumulating evidence suggests that oxidative stress is implicated in AD; Ab generates reactive oxygen species leading to mitochondrial dysfunctions in vitro (Lustbader et al, 2004;Manczak et al, 2010).…”

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

“…Finally, JIP3 KO i 3 Neurons showed a large increase in the total levels of tau and even more so in the phosphorylation of multiple sites on tau that exhibit hyperphosphorylation in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia (Congdon and Sigurdsson, 2018;Edwards, 2019;Grundke-Iqbal et al, 1986;Long and Holtzman, 2019). How JIP3 mutations lead to the increases in tau levels and phosphorylation on multiple sites remains to be determined.…”

Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia

“…Amyloid that accumulates within the vasculature, CAA, and brain parenchyma, forms plaques (AD) that disrupt the distribution of perlecan (Table 3) [147][148][149], decreases the ability of SMC to bind perlecan [150], and contributes to vascular wall weakening [147]. Modifications to the sulfate content of the specific GAG chains of perlecan were also found to be critical to the binding of amyloid [151].…”