As the telomeres shorten with age, some proteins misfold into amyloids, whose buildup a main cause of death of supercentenarians. 1 Amyloids are most damaging to the brain, beyond white blood cells, where they cause Alzheimer's disease (AD). The brain is easily damaged by inflammation, so that pathogens must be prevented from entering it at all by the blood-brain barrier (BBB). All of us make amyloids as we age, but only when the BBB is damaged do they cause AD. The symptoms are managed by reducing inflammation with antiglutamatergics and by restoring signaling with cholinergics, but this does not treat the cause.
BBB damage can be caused by a number of preventable factors (saturated fat, 5 alcohol, 19 drugs, 20 21 22 ischemia, 2 hypertension, 3 oxidative stress, 4 inflammation 6, sleep deprivation, 24 low gut flora 25) but one non-preventable factor in all cases of AD is menopause, 18 and because sex hormones cause tolerance, menopause is best treated instead with sex hormone releasers like clomiphene. However, once the BBB is damaged, matrix metalloproteinases (MMPs) (which remove proteins in the extracellular matrix) can prevent repair, so that once the BBB is no longer being damaged, it must be repaired with MMP inhibitors such as tetracyclines 8 9 10 11 12 13 or caffeine. 14 Signs of AD can be seen in the hippocampus decades beforehand 15 because its severity depends on how many amyloids there are to pass through the BBB in the first place, and as the memory center, the hippocampus depends on neurogenesis, 16 which is reduced by amyloids 17 even in small amounts. Strokes also damage the blood-brain barrier, hence they can cause vascular dementia.
1 Department of Pathology and Laboratory Medicine performs autopsy on 115-year-old woman to aid research
2 Abulrob et al.: In vivo optical imaging of ischemic blood-brain barrier disruption.
3 Ito et al.: Effect of Hypertension on Blood-Brain Barrier Change after Restoration of Blood Flow in Post-Ischemic Gerbil Brains An Electronmicroscopic Study
4 Lochhead et al.: Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation.
5 Martha Clare Morris: Diet and Alzheimer's Disease: What the Evidence Shows
6 EurekaAlert: Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155
7 Jangula et al.: Lipopolysaccharide-induced blood brain barrier permeability is enhanced by alpha-synuclein expression
8 Ferretti et al.: Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology
9 Loeb MB et al.: A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease.
10 Khlistunova et al.: Inducible Expression of Tau Repeat Domain in Cell Models of Tauopathy
11 Choi et al.: Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models
12 Costa et al.: Testing the Therapeutic Potential of Doxycycline in a Drosophila melanogaster Model of Alzheimer Disease
13 Hunter et al.: Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning
14 Arendash, Cao: Caffeine and coffee as therapeutics against Alzheimer's disease.
15 Kunz et al.: Reduced grid-cell–like representations in adults at genetic risk for Alzheimer’s disease
16 Bruel-Jungerman et al.: Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses.
17 Haughey et al.: Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.
18 Wilson et al.: Reproductive hormones regulate the selective permeability of the blood-brain barrier
19 J. Haorah: Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction
20 Christer Carlsson: Blood-brain barrier dysfunction after amphetamine administration in rats
21 Servio H Ramirez: Methamphetamine disrupts blood–brain barrier function by induction of oxidative stress in brain endothelial cells
22 Hari Shanker Sharma: Acute Administration of 3,4-Methylenedioxymethamphetamine Induces Profound Hyperthermia, Blood–Brain Barrier Disruption, Brain Edema Formation, and Cell Injury
23 Chen et al.: Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer’s and Parkinson’s disease
24 Journal of Neuroscience, Junyun He et al.: Sleep Restriction Impairs Blood–Brain Barrier Function
25 Braniste V et al.: The gut microbiota influences blood-brain barrier permeability in mice