New Insights Into the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.

Keywords: Alzheimer's disease; amyloid; gamma rhythm; ghrelin; infection; pericytes; prions; tauopathies.

Figure 1

Schematic diagram of the progressive cleavages of the amyloid beta (Aβ) precursor protein (APP) transmembrane domain. Aβ peptide is generated from APP processing via the amyloidogenic pathway (B). (A,C) are non-amyloidogenic pathological pathway under physiological conditions.

Figure 2

A series of studies from Li-Huei Tsai indicating that gamma stimulations ameliorate pathology and cognitive impairment in Alzheimer's disease (AD). (A) Gamma induced by optogenetic stimuli reduced amyloid beta (Aβ) production in CA1, increased number and cell body diameter of microglia, and reduced the process length of microglia compared with the control group, indicating an engulfing state of microglia. The percentage of microglia co-localized with Aβ in the cell body increased, suggesting that gamma stimulation triggers microglia to increase Aβ uptake. (B) Gamma induced by light flicker reduces Aβ levels and plaque load in the visual cortex (VC). Microglia changes similar to (A), except that the number does not change. (C) In 5xFAD mice, 40-Hz auditory stimulation improves memory performance and reduces amyloid load and tau phosphorylation and seeding in the auditory cortex (AC) and hippocampus. The changes of microglia similar to (A) and the number of astrocytes increased. Furthermore, blood vessel diameter increased. (D) Combined auditory and visual stimulation induces a clustering phenotype response by microglia and reduces amyloid load across broad cortical regions.

Figure 3

Pathways regulating growth hormone secretagogue receptor 1α (GHSR1α)/dopamine receptor D1 (DRD1) interaction by amyloid beta (Aβ) in the hippocampus of patients with Alzheimer's disease (AD). Aβ binds directly to GHSR1α and inhibits the activation of GHSR1α and prevented GHSR1α/DRD1 heterodimerization, resulting in synaptic plasticity damage and memory loss. In a mouse model of AD, simultaneous use of the selective GHSR1α agonist MK0677 and the selective DRD1 agonist SKF81297 rescued GHSR1α function from Aβ inhibition, thereby reducing hippocampal synaptic damage and improving spatial memory.

Figure 4

Pathways regulating contractile process of a pericyte around a capillary in the brain. Amyloid beta (Aβ) generates reactive oxygen species (ROS) (via NOX4), which evoke the release of endothelin (ET)-1, which can activate contraction by binding to ETA. These lead to the release of Ca2⁺, which evokes contraction of pericytes and brain capillaries, which leads to a decrease of the glucose and oxygen supply to the brain tissue. This pathway can be inhibited by blocking NOX4 with GKT137831 (GKT), blocking ETA receptors with BQ-123, and blocking the ET-evoked contraction by C-type natriuretic peptide (CNP).

Figure 5

Porphyromonas gingivalis in Alzheimer's disease brains. Porphyromonas gingivalis were identified in the brain of Alzheimer's disease patients and relate to Aβ, tau, and APOE by gingipains. (A) Loss of biological function of Aβ as an antimicrobial peptide after APP mutation may lead to further infections. The infection with P. gingivalis results in brain infection of mice and induction of A1-42, which is toxic to host cells. (B) Gingipain proteolysis cause direct damage or activation of procaspase-3 (which can be cleaved to activate caspase-3), resulting in Tau phosphorylation and tau cleavage change. (C) APOE4 may be more vulnerable to gingipain cracking, producing neurotoxic APOE fragments and resulting in decreased innate immune function.