Biochemistry of Alzheimer's disease
Although little is known about the process of filament assembly, depletion of a prolyl isomerase protein in the parvulin family has been shown to accelerate the accumulation of abnormal tau.
Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid.
[18] Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta plaques and tau-protein tangles.
[4] Although amyloid beta monomers are harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils[7] that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.
While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause.
The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss.
[37] This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster in vitro correlate with earlier onset and greater cognitive impairment in mouse models[38] and with AD diagnosis in humans.
[clarification needed] A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species, possibly toroidal or star-shaped with a central channel[40] that may induce apoptosis by physically piercing the cell membrane.
[42] A related alternative suggests that a globular oligomer localized to dendritic processes and axons in neurons is the cytotoxic species.
[49] Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits synaptic transmission, a pathophysiology that characterizes AD (in its early stages), by activating casein kinase 2.
[55] Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning[63] and eventually cause neuronal death.
[71][72] Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer's disease, compared with age-matched controls.
Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer's disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices.
Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease.
[70] In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer's disease.
Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.
[85] Reactive oxygen species (ROS) over-production is thought to play a critical role in the accumulation and deposition of amyloid beta in AD.
[90] DSBs are present in both neurons and astrocytes in the postmortem human hippocampus of AD patients at a higher level than in non-AD individuals.
[91] AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward.
[92] DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa.
[94] The cholesterol is produced in the astrocytes and shipped to neurons where it activates amyloid production through a process called substrate presentation.
The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD (including old age, ApoE4, Aβ, brain trauma, high blood pressure, smoking, type 2 diabetes, obesity, alcohol, stress and sleep deprivation), most of which are also associated with damage to the BBB.
It goes back a step to argue that the cause of the amyloid plaques, neurofibrillary/tau tangles and many other features of the disease is the invasion of Low-density lipoprotein (LDL) and other forms of 'bad cholesterol' along with free fatty acids (FFAs) into the brain, following breakdown of the BBB.
[108][109] The LIM argues that the influx of 'bad cholesterol' is the primary cause of the excess Aβ, plaque formation and neurofibrillary/tau tangles in Late Onset AD (LOAD), due to changes in lipid raft composition and endosomal-lysosomal trafficking.
This concurs with a large body of evidence showing an association of excess cholesterol with increased Aβ production, amyloid plaques [110][111] and neurofibrillary/tau tangles.
The LIM argues that the impact of the FFAs could cause most of the memory loss in AD, in addition to the spatial confusion, sleep disruption and sometimes paranoia also associated with the disease.
[115][116] A relatively recent hypothesis based mainly on rodent experiments links the onset of Alzheimer's disease to the hypofunction of the large extracellular protein reelin.
[121] A bioinformatics analysis in 2017[122] revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture.
As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site.
The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.
